CN102558147B

CN102558147B - Compound, and preparation method and application thereof

Info

Publication number: CN102558147B
Application number: CN201010604750.1A
Authority: CN
Inventors: 丛欣; 黄伟; 王鹏; 刘兆刚; 明志会; 施敏锋; 马玉恒; 沈超; 唐锋
Original assignee: Jiangsu Simcere Pharmaceutical R&D Co Ltd
Current assignee: Hainan Simcere Pharmaceutical Co ltd
Priority date: 2010-12-23
Filing date: 2010-12-23
Publication date: 2014-09-17
Anticipated expiration: 2030-12-23
Also published as: CN102558147A

Abstract

The invention provides a compound with the structure shown in a formula I, a preparation method of the compound, and an application of the compound as a tyrosine kinase and/or serine-threonine kinase inhibitor. The compound has a good inhibitory action on the activity of multiple kinases, and has an obvious inhibitory effect on tyrosine kinase and/or serine-threonine kinase in biochemical level and cell level in vitro (P is less than 0.05), and the half inhibitory concentration (IC50) for c-Met kinase is commonly below 10<-6>mol/L; and the compound also has an obvious inhibitory effect on proliferation of multiple tumor cells (P is less than 0.05), and the IC50 is respectively below 10<-5>mol/L. The compound with the structure shown in the formula I can be applied to preparing medicines for treating diseases related to protein kinase in organisms. The formula I is shown in the specification.

Description

Compound, preparation method and application

Technical field

The present invention relates to biomedicine field, particularly a compounds and preparation method, and the application of this compound in preparing tyrosine kinase inhibitor or serine-threonine kinase inhibitor.

Background technology

Between mammalian cell, there is similar molecular mechanism, within the whole cell cycle, regulate propagation, differentiation and the death of cell.Wherein, protein phosphorylation is the main mechanism of cross-film or intracellular signal transduction, have the function of regulating cell circulation, and phosphorylation is subject to the control of protein kinase (PKs) and phosphoprotein phosphatase.Protein kinase (protein kinases) claims again protein phosphorylation enzyme (protein phosphakinase), it is the enzyme of a class catalytic proteins phosphorylation reaction, be current known maximum protein family, all kinases have a very conservative catalytic core and various regulation and control model.The effect of protein kinase is that γ-phosphate of ATP is transferred to specific amino-acid residue on their substrates.According to the specificity of these amino-acid residues, these kinases are divided into 4 classes, wherein two main classes are albumen serine/threonine kinase (STKs) and protein tyrosine kinase (PTKs).In eukaryote, between the acceptor of cell surface and endonuclear re-reading system, there is separation and the distance of physics, extracellular signal affects the effect of some protein kinase cascade system by acceptor, phosphorylation through multistep protein, finally change the activity of transcription factor, genetic transcription is activated or retardance.Wherein, protein tyrosine kinase and albumen serine/threonine kinase have vital role in Normocellular signal transduction mechanism, their unconventionality expression will cause the generation of numerous disease, as tumour, arteriosclerosis, psoriasis and inflammatory reaction etc., thereby regulate and control these kinase whose activity, recover physiological equilibrium and can be used as a kind of new treatment means.

Family tyrosine kinase with transmembrane receptor (receptor tyrosine kinase, RTKs) or kytoplasm form (nonreceptor tyrosine kinase CTKs) participates in cell signalling widely.In human genome, protein kinase group comprises 30 kinds of family tyrosine kinases, contains altogether 90 kinds of different protein tyrosine kinases, and wherein 58 kinds is receptor tyrosine kinase.Different according to their structure, receptor type tyrosine kinase can be divided into 9 types, wherein common are 4 types:

EGF-R ELISA (EGFR) family: EGF-R family member comprises that EGF-R(molecular weight is 170kDa, and wide expression is in Various Tissues cell), erbB2/neu and erbB-3 gene expression product.Its family member's feature is to have two regions of being rich in halfcystine outward at after birth, and endochylema contains a region that has Tyrosylprotein kinase reactivity.

Insulin Receptor Family: its family member comprises insulin receptor (insulin receptor, IR), IGF-1R (insulin-like growth factor-1receptor, IGF-1R) and Regular Insulin associated receptor (insulin related receptor, IRR).Insulin Receptor Family member is the allos tetramer being formed by interchain disulfide bond by two alpha subunit He Erge β subunits.Wherein alpha subunit is ligand binding site; In the endochylema of β subunit, part contains tyrosine kinase activity region.

PDGF/MCSF/SCF receptor family: its family member comprises platelet-derived growth factor ' alpha ' acceptor (PDGF-α R), PDGF-β R, macrophage colony-stimulating factor receptor (M-CSFR) and stem cell factor acceptor (SCFR).Above member's feature is that after birth contains 5 immunoglobulin like domain outward, and endochylema contains two butyric acid kinase function districts that are cascaded structure.

Fibroblast growth factor acceptor (FGFR) family: FGFR family member has FGFR1, FGFR2, FGFR3 and FGF4.Their feature is to contain 3 immune globulin spline structure territories outward at after birth, wherein between the 1st and the 2nd structural domain, has one containing 8 continuous acidic amino acid structures, claims again acid box structure domain (acid box domain); Endochylema contains two cruel propylhomoserin kinase function districts that are cascaded structure.

Receptor tyrosine kinase is the transmembrane protein that a class has kytoplasm region, and extracellular region is ligand structure territory, and part is solubility or membrane-bound polypeptide or protein hormone, comprises Regular Insulin and multiple somatomedin.Born of the same parents' inner segment is the catalytic site of protein tyrosine kinase, and has autophosphorylation site, and its inherent catalytic activity is activated when with ligand binding.This receptoroid mainly contains c-Met(pHGF), EGFR(EGF-R ELISA), VEGFR(vascular endothelial growth factor receptor), PDGFR(platelet derived growth factor receptor), FGFR(fibroblast growth factor acceptor) etc.Most important downstream signal cascade reaction is to be activated by receptor tyrosine kinase, comprising ERK/MAPK signal path, and PI-3 kinases-AKT signal path and JAK/STAT signal path.Receptor tyrosine kinase maintains mutual signal and communication in all these different transduction pathway, the transcribing of final regulation and control gene.In addition, other cascade reaction also can be used.The regulation mechanism of nonreceptor tyrosine kinase differs greatly, they by with the effect of transmembrane receptor generation physical property, and then participate in extracellular signal response (Grosios k, et al, Drugs Fut, 2003,28:679).In many intracellular signal proteins (as Shc, Grb2, Src, Cbl, Phospholipase C g and 3 '-Phosphoinoside kinase [PI-3kinase] etc.), these tyrosine residuess that are phosphorylated are present in the calmodulin binding domain CaM of Tyrosine O-phosphate as docking site.The mixture that these are activated in cytolemma impels initial signal cascade reaction, and this has crucial effect to downstream signal and biological effect.If receptor deficiency catalytic activity, can with the coupling of nonreceptor tyrosine kinase phase, the kytoplasm region by non-covalent associating and a receptor subunit forms " binary acceptor ".Most important downstream signal cascade is to be activated by receptor tyrosine kinase, comprising ERK/MAPK signal path, and PI-3 kinases-AKT signal path and JAK/STAT signal path.Receptor tyrosine kinase maintains mutual signal and communication in all these different transduction pathway, the transcribing of final regulation and control gene.In addition, other cascade reaction also can be used, and for example insulin receptor (InsR) utilizes adenylyl cyclase signal transduction system, the serine-threonine Special Proteins kinases that activation cAMP relies on.

In normal cell, the rapid internalization of the receptor tyrosine kinase of activation is also left cell surface, thereby modification inhibitory enzyme activity occurs, and this activation of guaranteeing signal cascade reaction is of short duration, and cell can return to non-stimulation state in time.But the change of many structures, as the imbalance of single amino acids replacement and the amino acid whose disappearance of large section or Inhibitory signal and self-acting control mechanism, can cause kinases and catalysis region thereof to continue in active state.The receptor tyrosine kinase sustained activation that numerous disease causes to this sudden change and PTKs false demonstration or overexpression are relevant.In the characterization of molecules process of malignant tumour, find nearly half known PTKs, such as c-Met, EGFR, ErbB2, Ret, Kit, Src, Abl, PDGFR, VEGF1/2/3, FGFR1/2/3 etc., all exists and suddenlys change or the situation of overexpression.Meanwhile, the overexpression of clinical studies show Tyrosylprotein kinase or imbalance to prediction tumour patient and symptom have important references be worth (Madhusudan S, et al, Clin Biochem, 2004,37:618).From the above mentioned, Tyrosylprotein kinase is very important to the autologous adjusting of physiology, and transgenation/rearrangement can make PTKs extremely or overexpression, thereby causes the generation of disease, therefore can use the agonist of these enzymes or antagonist to treat.

That potential gene alteration or the existence of abnormal receptor all can have disease phenotype (for example cancer) separately, and relevant with extracellular signal transmission in cell cycle and born of the same parents, for example paracrine and Autocrine transmission.The overexpression of somatomedin (for example c-Met, EGF, VEGF, PDGF) acceptor and somatomedin often causes propagation and tumor-blood-vessel growth and the transfer of tumour cell.

Met is an important member in family tyrosine kinase, belongs to receptor tyrosine kinase (RTK), and Met is considered to tumorigenesis fusion rotein (TPR-MET) at first, proves now pHGF (Hepatocyte growth factor, HGF; Claim again the discrete factor: Scatter Factor, SF) unique high-affinity receptor.After HGF and Met specific binding, by induction Met albumen occurred conformation, change protein tyrosine kinase (PTK) structural domain in activated receptor intracellular region territory.The activation of Met can cause the tyrosine phosphorylation of multiple substrate protein, through compact cascade type phosphorylation reaction, signal is amplified step by step again, finally proceed to nucleus, cause a series of biological effects, especially can produce " invasive growth (invasive growth) " program of a kind of uniqueness.In vivo, this " invasive growth " program is relevant to biological effects such as cell proliferation survival, cell migration, inducing cell polarization, vascularization, injury repairing, tissue reconstructions.

In tumour occurs and develops, especially, for the tumour with invasion and attack and metastatic potential, HGF-Met signal path has played vital effect.Tumour cell can, by discharging the cytokines such as IL-1, FGF-2 and PDGF, stimulate contiguous fibroblasts to secrete HGF.Some tumour cell can be crossed expression Met and HGF by autocrine approach simultaneously.The expression of crossing of Met is found in people's cancer of the stomach, liver cancer, cholangiocarcinoma, carcinoma of the pancreas, lung cancer, thyroid carcinoma, pleura mesenchymoma etc.In there is the tumour shifting, HGF/Met signal path may affect: sticking between (1) tumour cell, promote the migration of tumour cell; (2) promote extracellular matrix degradation, thereby promote the transfer of tumour; (3) induction of vascular generates; (4) promoting mitosis, promotes cell proliferation by a plurality of signal paths.Therefore; take HGF/Met signal path as target; realization that can be relatively easy is disturbed to many paths time; once the HGF-Met signal path of abnormal activation overexpression in tumour cell is blocked; will there is cellular form and change in tumour cell, cause that increment slows down, becomes a series of variations of degradation under knurl reduction, invasive ability.

The discussion more detailed to Tyrosylprotein kinase, referring to Manning G, Science, 2002,298:1912.

Nonreceptor tyrosine kinase (CTKs): take src gene product as representative, also have in addition Yes, Fyn, Lck, Fgr, Lyn, Fps/Fes and Ab1 etc.After Xu, outside both, all the other non-receptor type protein tyrosine kinase Src family molecules reasons are about the protein of 60kDa, and between them, except 80 amino acid of N-terminal form differences, other parts are all closely similar.The regulation mechanism of nonreceptor tyrosine kinase (CTKs) differs greatly, and they are by with transmembrane receptor (as hormone, cytokine and growth factor receptors), physical property effect occurring, and then the response of participation extracellular signal.In the specified phase of cell cycle, when combining with extracellular part or cell adhesion composition, these acceptors are activated.

Crosstalking of the sudden change of protein kinase, signal protein is the pathology reason that causes tumour, equally also can cause the generation of Other diseases.In some immunodeficiency symptoms, can observe the mutagenicity inactivation of non-receptor tyrosine, for example the inactivation of JAK3 causes serious severe combined immunodeficiency (Leonard WJ, Nat Rev Immunol, 2001,1:200; Leonard WJ, Int J Hematol, 2001,73:271).Bruton protein tyrosine kinase (BTK or BPK, ATK) belongs to Src family, it is the ripe necessary a kind of Tyrosylprotein kinase of B cell development, and that Btk transgenation meeting causes is congenital without Immunoglobulinemia (Cheng G, et al, Proc Natl Acad Sci USA, 1994,91:8152; Maas A, et al, J Immunol, 1999,162:6526).

Tyrosine protein kinase also has important physiological action in central nervous system, its not normal generation that also can cause corresponding disease, for example, at alzheimer's disease (Alzheimer disease, AD) relevant (the Ferguson SS of immunoreactivity of neurone spot and neuregulin-1 (neuregulin-1) and ErbB4 in patient body, Trends Neurosci, 2003,26:119; Chaudhury AR, et al, J Neuropathol Exp Neurol, 2003,62:42).RhIGF-1 (IGFs) and adjusting albumen thereof are to be secreted by cardiovascular systems, these factor dysregulations can cause developing of coronary atherosclerosis and restenosis, and the effect of IGFs is mediated by specific membranes acceptor, wherein IGF receptor type I has tyrosine kinase activity, comes across the smooth muscle cell of atherosclerotic lesions, inflammatory cell and arterial endothelial cell (Bayes-genis A, et al, Circ Res, 2000,86:125; Bayes-genis A, et al, Artherio Thromb and Vascu Biol, 2001,21:335; Che WY, et al, Circ Res, 2002,90:1222).Vascular endothelial growth factor and acceptor thereof are expressed in the various kinds of cell of rheumatoid arthritis, and be key factor in rheumatoid arthritis rationality angiogenic process (De Bandt M, et al, J Immunol, 2003,1712:4853).Jak2 is endochylema nonreceptor tyrosine kinase, and JAK2 transgenation at least causes three kinds of diseases (Spivak JL, Blood, 2002,100:4272; Thiele J, et al, Acta Haematol, 2004,111:155)---polycythemia vera (PV), idiopathic myelofibrosis (IMF), primary thrombocytosis (ET) and some other myeloproliferative diseases that is not true to type (MPD).The trans-regional sudden change of fibroblast growth factor acceptor can cause the most common heredity nanism---and osteochondrodysplasia (Shiang R, et al, Cell, 1994,78:335).In addition, numerous disease with lack tyrosine signal correction, for example non-insulin-dependent diabetes mellitus (NIDDM) and peripheral neuropathy, and transmission by wild phase induction signal can effectively improve symptom (Hunter T, Cell, 2000,100:111).For some other and blood vessel, relevant disease occurs, for example some cardiovascular disorder, stimulates vasculogenesis than suppressing more effective.

Serine-threonine kinase (STKs) is the kinases family of a large class specificity catalytic protein Serine and threonine residues phosphorylation, numbering: EC2.7.1.37.The same with nonreceptor tyrosine kinase, serine-threonine kinase is dominate in cell, although only have several serine-threonine receptor kinases.Serine-threonine kinase is modal cytosol kinases, be kinases in tenuigenin part rather than in cytoplasmic organoid and cytoskeleton, bring into play their function, and then affect the inside biological chemistry of cell, often as the descending reaction to Tyrosylprotein kinase event.Serine-threonine kinase can participate in signalling process simultaneously, and the latter causes DNA and synthesizes and cause subsequently the mitotic division of cell proliferation.In addition serine-threonine kinase has related to polytype cancer, as mammary cancer (Cance et al, Int.J.Cancer, 1993,55,571) etc.

To sum up, Tyrosylprotein kinase and serine-threonine kinase all comprise related to cancer with host's pathological condition.Other pathological condition relevant with protein kinase also comprises that psoriasis, liver cirrhosis, diabetes, blood vessel generation, restenosis, ophthalmic diseases, rheumatoid arthritis and other inflammatory disease, Immunological diseases, cardiovascular disorder are as arteriosclerosis and multiple ephrosis.

Along with molecular biological research is goed deep into, on molecular level, for cell signalling, the function of the growth regulation factor and regulation and control oncogene are the effective ways that suppresses cell proliferation and treat tumour.This approach can weaken the effect of improper signalling channel, stops the growth of tumour, also can impel death of neoplastic cells simultaneously.Find that there is so far half proto-oncogene and on encoding histone, all there is tyrosine structure, they participate in cell signalling by phosphorylation and dephosphorylation, simultaneously in tumour generating process, the Tyrosylprotein kinase of variation or overexpression can change normal cell into cancer cells, promotes growth and the mitotic division of tumour cell simultaneously.Because Tyrosylprotein kinase and serine-threonine kinase have important effect in the carinogenicity conversion process of cell, and have directly or indirectly and contact with the generation of tumour and development, the treatment that therefore tyrosine kinase inhibitor or serine-threonine kinase inhibitor is applied to tumour is particularly suitable.

Kinases inhibitor is the compound of a class arrestin kinase activity.Kinases inhibitor is divided into serine/threonine protein kitase inhibitor and tyrosine protein kinase inhibitor according to the kinase whose kind of arrestin, the former again can be according to site of action, be divided into three groups, one group acts on catalytic domain, one group acts on regulatory region, and another group all has effect to regulatory region and catalytic domain.

Pyridione derivatives has biological activity widely, in fields such as medicine, agricultural chemicals, has important application.In recent years, many pyridinone micromolecular compounds have been used as kinases inhibitor, be widely used in the multiple disease relevant to aberrant kinase activity for the treatment of, if tumour, psoriasis, liver cirrhosis, diabetes, blood vessel generation, ophthalmic diseases, rheumatoid arthritis and other inflammatory disease, Immunological diseases, cardiovascular disorder are as arteriosclerosis and multiple ephrosis.Wherein, 3-alkynyl pyridine compounds (PCT WO2008008493), 5-aromatic yl pyridine ketone compound (PCT WO2008008493, WO2008103277, WO2005097750), 3-aromatic yl pyridine ketone compound (PCT WO2004060890), aminopyridine ketone compounds (PCT WO2007044084, WO2007129040, WO2007035428), 6-aminopyridine ketone compounds (PCT WO2007044084, WO2007035428) and other pyridine compounds (PCT WO2008058229, WO2009149188, WO2008005457, WO2007006591) etc. all for Tyrosylprotein kinase and/or serine-threonine kinase inhibitor.But 2-pyridine compounds is used for the treatment of Tyrosylprotein kinase and/or serine-threonine kinase inhibitor have not been reported.

2-pyridone, 2(1H)-pyridone and 2-oxo pyridine, molecular formula is C ₅h ₅nO, molecular weight is 95.10, to photaesthesia, is dissolved in ethanol, chloroform, water and benzene, is slightly soluble in ether and petroleum naphtha, 106～107 ℃ of fusing points, 280～281 ℃ of boiling points, irritant, there is following chemical structure.

2-pyridone is not only the Multiple Pesticides of exploitation in recent years, important intermediate and the raw material of medicine; be simultaneously also by methyl alcohol synthesizing alcohol and acetaldehyde, prepare the important catalyst of introducing N-carbobenzoxy or N-4-nitrobenzyl ester group in the novel method of polyimide and protected amino acid.The technique of the synthetic 2-pyridone of tradition is that to take pyridine and sodium amide be raw material, through Chichibabin reaction, diazotization reaction and nucleophilic substitution reaction, completes.Therefore, provide a kind of 2-pyridine compounds and preparation method thereof, and this compound is as the purposes of Tyrosylprotein kinase and/or serine-threonine kinase inhibitor, significant.

Summary of the invention

The invention provides compounds and preparation method thereof, and this compound is as the purposes of Tyrosylprotein kinase and/or serine-threonine kinase inhibitor.This compound in vitro biochemistry level and cellular water on average has remarkable inhibition (P<0.05) to Tyrosylprotein kinase and/or serine-threonine kinase, and remarkable anticancer propagation (P<0.05).

In order to realize foregoing invention object, the invention provides following technical scheme:

The invention provides structure suc as formula the compound shown in I or its pharmacy acceptable salt,

Wherein, W and X are independently selected from C or N; If W, X are C, n is 0-4; If W or X are N, n is 0-3; If W, X are N, n is 0-2;

M is 0-3; B is O, NR ⁴, NR ⁴cH ₂, S, SO, SO ₂, CR ⁵r ⁶;

R ¹and R ²independently be selected from hydrogen, halogen, cyano group, NO ₂, OR ⁷, NR ⁸r ⁹, cycloalkyl, the aryl of alkyl, substituted alkyl, cycloalkyl, replacement be, the Heterocyclylalkyl of the aralkyl of the heterocyclic radical of the heteroaryl of the aryl of replacement, heteroaryl, replacement, heterocyclic radical, replacement, aralkyl, replacement, Heterocyclylalkyl, replacement;

R ⁴, R ⁸and R ⁹independently be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or substituted heterocyclic radical;

R ⁵and R ⁶independently be selected from the Heterocyclylalkyl of hydrogen, halogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, substituted heterocyclic radical, Heterocyclylalkyl or replacement;

R ⁷be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, allyl group, substituted allyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or substituted heterocyclic radical;

R ³be selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyl, alkoxyl group (OR ¹⁰), aryloxy, heteroaryloxy, benzyloxy, halogenated alkoxy ,-NR ¹⁰r ¹¹,-N (CH ₂) _p(R ¹²) (CH ₂) _pr ¹³,-NR ¹⁴c (O) R ¹⁵, aryl, heteroaryl; P is 0-3;

R ¹⁰and R ¹¹independently be selected from heterocyclic radical, the aralkyl of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement, Heterocyclylalkyl or the R of the aralkyl of replacement, Heterocyclylalkyl, replacement ¹⁰and R ¹¹the heterocyclic radical forming;

R ¹², R ¹³, R ¹⁴and R ¹⁵independently be selected from heterocyclic radical, the aralkyl of hydrogen, cyano group, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement;

A is selected from following group:

R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ²⁶, R ²⁷, R ²⁸, R ²⁹, R ³⁰, R ³¹, R ³², R ³³, R ³⁴, R ³⁵, R ³⁶, R ³⁷, R ³⁸, R ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³, R ⁴⁴, R ⁴⁵, R ⁴⁶, R ⁴⁷, R ⁴⁸, R ⁴⁹, R ⁵⁰, R ⁵¹, R ⁵², R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶and R ⁶⁷independently be selected from is hydrogen, halogen, haloalkyl, nitro, cyano group, OR ⁶⁸, NR ⁶⁹r ⁷⁰, CO ₂r ⁷¹,-C (O) NR ⁷²r ⁷³, SO ₂r ⁷⁴, S (O) ₂nR ⁷⁵r ⁷⁶, NR ⁷⁷s (O) ₂r ⁷⁸, NR ⁷⁹c (O) R ⁸⁰, NR ⁸¹cO ₂r ⁸²,-CO (CH ₂) _rr ⁸³,-CONH (CH ₂) _rr ⁸⁴, SR ⁸⁵, SOR ⁸⁶, heterocyclic radical, the aralkyl of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement be, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement; R is 0-4;

R ⁶⁸, R ⁶⁹, R ⁷⁰, R ⁷¹, R ⁷², R ⁷³, R ⁷⁴, R ⁷⁵, R ⁷⁶, R ⁷⁷, R ⁷⁸, R ⁷⁹, R ⁸⁰, R ⁸¹, R ⁸², R ⁸³, R ⁸⁴, R ⁸⁵and R ⁸⁶independently be selected from heterocyclic radical, the aralkyl of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement;

G is O, S or NR ⁸⁷; D is CR ⁸⁸or N; Z is N or CR ⁸⁹;

R ⁸⁷, R ⁸⁸and R ⁸⁹independently be selected from heterocyclic radical, the aralkyl of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylsulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement.

Alkyl represents the saturated aliphatic radical of 1-20 carbon atom, comprises straight chain and branched group, and the alkyl that contains 1-4 carbon atom is called low alkyl group.When low alkyl group does not have substituting group, be called unsubstituted low alkyl group.More preferably, alkyl is the medium sized alkyl that has 1-10 carbon atom, as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl, amyl group etc.Most preferably, alkyl is the low alkyl group that has 1-4 carbon atom, as methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted, when being the alkyl replacing, this substituting group preferably one or more, more preferably 1-3,1 or 2 substituting group most preferably, described substituting group is independently preferably from following group: halogen, hydroxyl, lower alkoxy, aryl, aryloxy, heteroaryl, heterolipid cyclic group ,-C (O) R ⁷,-NR ⁸r ⁹with-C (O) NR ¹¹r ¹², R wherein ⁷, R ⁸, R ⁹, R ¹¹and R ¹²define the same.

Cycloalkyl represents to be all the monocycle of carbon or the ring condensing, described fused rings refers to each ring and shares with other ring in system a pair of carbon atom adjoining, wherein one or more rings do not have the π-electron system connecting completely, and cycloalkyl comprises cyclopropane, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, diamantane, cyclohexadiene, suberane and cycloheptatriene.Cycloalkyl can be replacement with unsubstituted; when being substituted; substituting group is preferably one or more independently selected from following group: alkyl, aryl, heteroaryl, heterolipid cyclic group, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkane sulfydryl, aromatic thiohydroxy, cyano group, halogen, carbonyl, thiocarbonyl, C-carboxyl, O-carboxyl, O-formamyl, N-formamyl, C-amido, N-amido, nitro, amino and-NR ⁸r ⁹, R wherein ⁸and R ⁹define the same.

Aryl represents full carbon monocycle or the fused polycycle group of 1 to 12 carbon atom, has the π-electron system of total conjugated.Aryl comprises phenyl, naphthyl and anthryl, can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more, more preferably one, two or three, and then more preferably one or two, independently selected from by low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyano group, acyl group, sulfo-acyl group, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R ⁸s (O)-, R ⁸s (O) ₂-,-C (O) OR ⁸, R ⁸c (O) O-and-NR ⁸r ⁹the group forming, R ⁸and R ⁹define the same.Preferably, aryl is replaced by one or two substituting group alternatively, and substituting group is independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, sulfydryl, cyano group, N-amido, list or dialkyl amino, carboxyl or N-sulfonamido.

Heteroaryl represents monocycle or the fused rings group of 5 to 12 annular atomses, contains one, two, three or four ring hetero atoms that are selected from N, O or S, and all the other annular atomses are C, have in addition the π-electron system of total conjugated.Unsubstituted heteroaryl ground limiting examples has pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyrimidine, pyridine, quinoline, isoquinoline 99.9, quinazoline, thienopyridine, Thienopyrimidine, pyrrolopyridine, purine, tetrazolium, triazine and carbazole.Heteroaryl can be that replace or unsubstituted; when being substituted; substituting group is preferably one or more; more be preferably one, two or three; and then more preferred one or two, be independently selected from following group: low alkyl group, three alkylhalide groups, halogen, hydroxyl, alkoxyl group, sulfydryl, (low alkyl group) sulfenyl, alkynyl, cyano group, acyl group, sulfo-acyl group, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R ⁸s (O)-, R ⁸s (O) ₂-,-C (O) OR ⁸, R ⁸c (O) O-and-NR ⁸r ⁹, R wherein ⁸and R ⁹define the same.Preferred heteroaryl is replaced by one or two substituting group alternatively, and substituting group is independently selected from halogen, alkoxyl group, alkynyl, amino, benzyloxy, aryl.

Heterolipid cyclic group represents monocycle or fused rings group, has 5 to 9 annular atomses in ring, and wherein one or two annular atoms is to be selected from N, O or S (O) _mthe heteroatoms of (wherein m is 0 to 2 integer), all the other annular atomses are C.These rings can have one or more pair of key, but these rings do not have the π-electron system of total conjugated.Unsubstituted heterolipid cyclic group comprises pyrrolidyl, piperidino-(1-position only), Piperazino, morpholino base, thiomorpholine Dai Ji etc.Heterolipid cyclic group can be that replace or unsubstituted; when being substituted; that substituting group is preferably is one or more, more preferably one, two or three; and then more preferably one or two, independently selected from following group: low alkyl group, three alkylhalide groups, halogen, hydroxyl, lower alkoxy, sulfydryl, (low alkyl group) sulfenyl, cyano group, acyl group, sulfo-acyl group, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonamido, S-sulfonamido, R ⁸s (O)-, R ⁸s (O) ₂-,-C (O) OR ⁸, R ⁸c (O) O-and-NR ⁸r ⁹, R wherein ⁸and R ⁹define the same.Preferably, heterolipid cyclic group is replaced by one or two substituting group alternatively, and substituting group is independently selected from halogen, low alkyl group, three alkylhalide groups, hydroxyl, sulfydryl, cyano group, N-amido, list or dialkyl amino, carboxyl or N-sulfonamido.

Heterocyclic radical represents the saturated cyclic group of 3 to 8 annular atomses, and wherein one or two annular atoms is to be selected from N, O or S (O) _mthe heteroatoms of (wherein m is 0 to 2 integer), all the other annular atomses are C, wherein one or two C atom can be replaced by carbonyl alternatively.The ring of heterocyclic radical can be alternatively replaced by one, two or three substituting groups independently, substituting group be selected from low alkyl group (replaced by one or two substituting group alternatively, substituting group is independently selected from carboxyl or ester group), haloalkyl, halogen, nitro, cyano group, hydroxyl, alkoxyl group, amino, monoalkyl amido, dialkyl amino, aralkyl, heteroaralkyl ,-C (O) R(wherein R be alkyl) and-(CH ₂) nY, wherein Y is heterolipid cyclic group and R ¹⁰, wherein n is 0 to 2 integer, R ¹⁰define the same.More specifically, heterocyclic radical comprises THP trtrahydropyranyl, 2,2-dimethyl-1,3-dioxolane, piperidino-(1-position only), N-methyl piperidine-3-base, Piperazino, N-methylpyrrolidin-3-base, pyrrolidyl, morpholino base, thiomorpholine are for base, thiomorpholine generation-1-oxide compound, thiomorpholine generation-1,1-dioxide, 4-ethoxycarbonyl Piperazino, 3-oxo Piperazino, 2-imidazolone, 2-Pyrrolidone, tetrahydropyrimidin-2-ones and derivative thereof.Preferably, heterocyclic group is replaced by one or two substituting group alternatively, substituting group is independently selected from halogen, low alkyl group, low alkyl group, the low alkyl group being replaced by heterolipid cyclic group, hydroxyl, list or the dialkyl amino and the heterolipid cyclic group that are replaced by hydroxyl, carboxyl or ester group, and wherein heterolipid cyclic group comprises pyrrolidyl, piperidino-(1-position only), Piperazino etc.

Represent-OH of hydroxyl group; The unsubstituted alkyl of represent-O-(of alkoxyl group) and-the unsubstituted cycloalkyl of O-(), comprise methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Represent-O-of aryloxy aryl and-O-heteroaryl, comprise phenoxy group, pyridyloxy, furans oxygen base, thiophene oxy, 2-pyrimidinyl oxy, pyrazine oxygen base etc. and derivative thereof.Represent-O-of benzyloxy benzyl.Comprise without substituted benzyl, substituted benzyl etc. and derivative thereof; Represent-SH of sulfydryl group.

Represent-C of acyl group (O)-R ' group; wherein R ' is selected from: hydrogen, unsubstituted low alkyl group, trihalogenmethyl, unsubstituted cycloalkyl, alternatively by one or more, preferably by 1,2 or 3 be selected from unsubstituted low alkyl group, trihalogenmethyl, unsubstituted lower alkoxy, halogen and-NR ⁸r ⁹the aryl that the substituting group of group replaces, wherein R ⁸and R ⁹define the same, alternatively by one or more, preferably by 1,2 or 3 be selected from unsubstituted low alkyl group, trihalogenmethyl, unsubstituted lower alkoxy, halogen and-NR ⁸r ⁹the heteroaryl (by ring carbon atom bonding) that the substituting group of group replaces, and alternatively by one or more, preferably by 1,2 or 3 be selected from unsubstituted low alkyl group, trihalogenmethyl, unsubstituted lower alkoxy, halogen and-NR ⁸r ⁹the heterolipid cyclic group (by ring carbon atom bonding) that the substituting group of group replaces, representational acyl group comprises ethanoyl, trifluoroacetyl group, benzoyl etc.Represent-C of sulfo-acyl group (S)-R ' group, wherein R ' defines the same.Represent-C of ester group (O) O-R ' group, wherein R ' define the same, but R ' can not be hydrogen.Represent-C of ethanoyl (O) CH ₃group.

Halogen represents fluorine, chlorine, bromine or iodine.Represent-CX of trihalogenmethyl ₃group.Represent-CN of cyano group group.Represent-S of S-sulfonamido (O) ₂nR ⁸r ⁹group, wherein R ⁸and R ⁹define the same.Represent-NR of N-sulfonamido ⁸s (O) ₂r ⁹group, wherein R ⁸and R ⁹define the same.O-carbamyl basis representation-OC (O) NR ¹¹r ¹²group, wherein R ¹¹and R ¹²define the same.N-carbamyl basis representation R ⁸oC (O) NR ⁹-group, wherein R ⁸and R ⁹define the same.Represent-OC of O-thiocarbamoyl (S) NR ¹¹r ¹²group, wherein R ¹¹and R ¹²define the same.N-thiocarbamoyl represents R ⁸oC (S) NR ⁹-group, wherein R ⁸and R ⁹define the same.Amino expression-NH ₂group.Represent-C of C-amido (O) NR ⁸r ⁹group, wherein R ⁸and R ⁹define the same.N-amido represents R ⁸c (O) NR ⁹-group, wherein R ⁸and R ⁹define the same.Represent-NO of nitro ₂group.Haloalkyl represents that the preferred low alkyl group as defined above of alkyl is replaced by one or more identical or different halogen atoms, for example-CH ₂cl ,-CF ₃,-CCl ₃,-CH ₂cF ₃,-CH ₂cCl ₃deng.Haloalkoxy basis representation alkoxyl group, preferably as defined above-O-alkyl, wherein alkyl is replaced by one or more identical or different halogen atoms, preferred three halogen methoxyl groups, as-OCF ₃.Aralkyl represents alkyl, preferred low alkyl group as defined above, and it is replaced by aryl as defined above, for example-CH ₂phenyl ,-(CH ₂) ₂phenyl ,-(CH ₂) ₃phenyl, CH ₃cH (CH ₃) CH ₂phenyl and derivative thereof.Heteroaralkyl represents alkyl, preferred low alkyl group as defined above, and it is replaced by heteroaryl, for example-CH ₂pyridyl ,-(CH ₂) ₂pyrimidyl ,-(CH ₂) ₃imidazolyl etc. and derivative thereof.Monoalkylamine basis representation group-NHR, wherein R is alkyl or unsubstituted cycloalkyl as defined above, such as methylamino, (1-methylethyl) amido, cyclohexylamino etc.Dialkylamine basis representation group-NRR, wherein each R is alkyl or unsubstituted cycloalkyl as defined above independently, such as dimethyl amido, diethyl amido, N-methylcyclohexyl amido etc.

Piperazino refers to the group with following chemical structure.

Morpholino base refers to the group with following chemical structure.

Piperidino-(1-position only) refers to the group with following chemical structure.

Pyrrolidyl refers to the group with following chemical structure.

As preferably, structure provided by the invention is suc as formula in the compound shown in I, and B is selected from O, S or NHR ⁴;

As preferably, structure provided by the invention is suc as formula in the compound shown in I, and X is selected from C, R ¹for hydrogen or halogen;

As preferably, structure provided by the invention is suc as formula in the compound shown in I, and X is N;

As preferably, structure provided by the invention is suc as formula in the compound shown in I, and A is selected from the pyridine of replacement or quinoline, quinazoline, thienopyridine, Thienopyrimidine, Pyrazolopyridine;

As preferably, structure provided by the invention is suc as formula in the compound shown in I, and A is aminopyridine;

Structure provided by the invention is suc as formula the compound shown in I or its pharmacy acceptable salt, and as preferably, structure can be suc as formula shown in II:

Wherein, X is selected from C or N; B is selected from O, S or NH; R ¹be selected from hydrogen or halogen; R ²be selected from hydrogen or OR ⁷; R ⁷be selected from hydrogen, alkyl, substituted alkyl, allyl group or substituted allyl;

R ³be selected from hydroxyl, alkoxyl group ,-NR ¹⁰r ¹¹or-N (CH ₂) _p(R ¹²) (CH ₂) _pr ¹³; P is 0-2;

R ¹⁰and R ¹¹independently be selected from heterocyclic radical or the R of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement ¹⁰and R ¹¹the heterocyclic radical forming;

R ¹²and R ¹³independently be selected from the heterocyclic radical of hydrogen, cyano group, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or replacement;

A is selected from following group:

R ¹⁶, R ¹⁷, R ¹⁸, R ²⁶, R ²⁷, R ²⁹, R ³⁰, R ³¹and R ³²independently be selected from hydrogen, halogen, haloalkyl, nitro, cyano group, OR ⁶⁸, NR ⁶⁹r ⁷⁰, CO ₂r ⁷¹,-C (O) NR ⁷²r ⁷³, SO ₂r ⁷⁴, S (O) ₂nR ⁷⁵r ⁷⁶, NR ⁷⁷s (O) ₂r ⁷⁸, NR ⁷⁹c (O) R ⁸⁰, NR ⁸¹cO ₂r ⁸²,-CO (CH ₂) _rr ⁸³,-CONH (CH ₂) _rr ⁸⁴, SR ⁸⁵, SOR ⁸⁶, heterocyclic radical, the aralkyl of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement be, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement; R is 0-4;

Z is selected from N or CR ⁸⁹; R ⁸⁹be selected from heterocyclic radical, the aralkyl of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylsulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement.

As preferably, the present invention also provides structure suc as formula the compound shown in III or its pharmacy acceptable salt,

Wherein, X is selected from C or N; If X is C, n is 0-4; If X is N, n is 0-3;

M is 0-3; B is O, NR ⁴, NR ⁴cH ₂, S, SO, SO ₂, CR ⁵r ⁶;

A is selected from following group:

R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ²⁶, R ²⁷, R ²⁸, R ²⁹, R ³⁰, R ³¹, R ³², R ³³, R ³⁴, R ³⁵, R ³⁶, R ³⁷, R ³⁸, R ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³, R ⁴⁴, R ⁴⁵, R ⁴⁶, R ⁴⁷, R ⁴⁸, R ⁴⁹, R ⁵⁰, R ⁵¹, R ⁵², R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶and R ⁶⁷independently be selected from hydrogen, halogen, haloalkyl, nitro, cyano group, OR ⁶⁸, NR ⁶⁹r ⁷⁰, CO ₂r ⁷¹,-C (O) NR ⁷²r ⁷³, SO ₂r ⁷⁴, S (O) ₂nR ⁷⁵r ⁷⁶, NR ⁷⁷s (O) ₂r ⁷⁸, NR ⁷⁹c (O) R ⁸⁰, NR ⁸¹cO ₂r ⁸²,-CO (CH ₂) _rr ⁸³,-CONH (CH ₂) _rr ⁸⁴, SR ⁸⁵, SOR ⁸⁶, heterocyclic radical, the aralkyl of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement be, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement; R is 0-4;

G is O, S or NR ⁸⁷; D is CR ⁸⁸or N; Z is N or CR ⁸⁹; R ⁸⁷, R ⁸⁸and R ⁸⁹independently be selected from heterocyclic radical, the aralkyl of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkylsulfonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement.

The present invention also provides the preparation method of structure suc as formula compound shown in III, and substrate is structure suc as formula compound shown in III A and structure suc as formula compound shown in III B,

Step 1: described substrate generating structure under the catalysis of DMAP, suc as formula the compound shown in III C, makes structure suc as formula the compound shown in V through basic hydrolysis;

Step 2: structure is reacted suc as formula replacing amine shown in III D with structure suc as formula compound shown in V, makes and states structure suc as formula the compound shown in III.

As preferably, the present invention also provides a kind of structure suc as formula the compound shown in IV or its pharmacy acceptable salt,

Wherein, X is selected from C or N; If X is C, n is 0-4; If X is N, n is 0-3;

M is 0-3;

R ⁸and R ⁹independently be selected from hydrogen, alkyl, substituted alkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or substituted heterocyclic radical;

A is selected from following group:

Wherein, R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ²⁶, R ²⁷, R ²⁸, R ²⁹, R ³⁰, R ³¹, R ³², R ³³, R ³⁴, R ³⁵, R ³⁶, R ³⁷, R ³⁸, R ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³, R ⁴⁴, R ⁴⁵, R ⁴⁶, R ⁴⁷, R ⁴⁸, R ⁴⁹, R ⁵⁰, R ⁵¹, R ⁵², R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶and R ⁶⁷independently be selected from hydrogen, halogen, haloalkyl, nitro, cyano group, OR ⁶⁸, NR ⁶⁹r ⁷⁰, CO ₂r ⁷¹,-C (O) NR ⁷²r ⁷³, SO ₂r ⁷⁴, S (O) ₂nR ⁷⁵r ⁷⁶, NR ⁷⁷s (O) ₂r ⁷⁸, NR ⁷⁹c (O) R ⁸⁰, NR ⁸¹cO ₂r ⁸²,-CO (CH ₂) _rr ⁸³,-CONH (CH ₂) _rr ⁸⁴, SR ⁸⁵, SOR ⁸⁶, heterocyclic radical, the aralkyl of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement be, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement; R is 0-4;

G is selected from O, S or NR ⁸⁷; D is selected from CR ⁸⁸or N; Z is selected from N or CR ⁸⁹;

The present invention also provides the preparation method of a kind of structure suc as formula compound shown in IV, substrate be structure suc as formula compound shown in IV A,

Step 1: described substrate reacts generating structure suc as formula compound shown in IV B with DMF dimethylacetal in DMF;

Step 2: described structure refluxes in ethanol suc as formula compound shown in compound shown in IV B and formula IV C,

Wherein, Bn is benzyl, and the compound making and halogenating agent, under the existence of acid binding agent, nucleophilic substitution occurs, then hydrolysis obtains structure suc as formula the compound shown in XI in aqueous sodium hydroxide solution;

Step 3: structure suc as formula the substituted heterocycle generation substitution reaction shown in IV D, makes structure suc as formula compound shown in IV suc as formula the compound shown in XI and structure.

As preferably, structure provided by the invention, suc as formula the compound shown in I, is specially:

Compound 1:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 2:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(3-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 3:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 4:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the chloro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides (I-4)

Compound 5:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(2-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 6:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 7:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the chloro-benzyl of-N-(3-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 8:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-cyano group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 9:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-benzyl-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 10:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(3-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 11:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 12:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 13:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 14:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 15:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-methyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 16:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the chloro-3-trifluoromethyl-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 17:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-phenyl) fluoro-benzyl-6-of-N-(4-oxo-1,6-dihydropyridine-3-acid amides

Compound 18:1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-isobutyl--6-oxo-1,6-dihydropyridine-3-acid amides

Compound 19:1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-tertiary butyl-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 20:1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-sec.-propyl-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 21:1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-(2-cyano ethyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 22:1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-(2-cyano methyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 23:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-cyano methyl)-N-(4-luorobenzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 24:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-5-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) pyridine-2(1H) ketone

Compound 25:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(furans-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 26:1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 27:1-(4-((2-amino-3-alkynyl pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 28:1-(4-((2-amino-3-(3-hydroxyl third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 29:1-(4-((2-amino-3-(3-dimethylamino third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 30:1-(4-((1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 31:1-(4-((2-methylol-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 32:1-(4-((dimethylamino methyl-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 33:1-(4-((2-(morpholinyl-methyl)-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 34:1-(4-((2-(piperidin-1-yl-methyl)-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

The fluoro-4-(thiophene of compound 35:1-(3-[3,2-d] pyrimidine-4-yl) oxo-phenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

The fluoro-4-(thiophene of compound 36:1-(3-[3,2-b] pyridin-7-yl) oxo-phenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 37:1-(4-(6,7-dimethoxyquinazoline-4-yl) the fluoro-phenyl of oxo 3-) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 38:1-(4-(6-benzyloxy-7-methoxyl group quinazoline-4-yl) the fluoro-phenyl of oxo 3-) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

The fluoro-4-(7-methoxyl group-6-(3-of compound 39:1-(3-morpholinyl-propoxy--quinazoline-4-yl) oxo-phenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 40:5 '-((2-amino-3-chloropyridine-4-yl) the fluoro-benzyl of oxo-N-(4-)-2-oxo-2H[1,2-dipyridyl]-5-acid amides

Compound 41:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 42:1-(4-((2-amino-3-chloropyridine-4-yl) oxo phenyl) the fluoro-benzyl of-N-(4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 43:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-4-oxyethyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 44:4-allyloxy-1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-4-oxyethyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 45:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-4-(2-methoxyethoxy)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 46:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-4-(2,3-dihydroxyl propoxy-) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 47:1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 48:1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-4-(2-methoxyethoxy)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 49:1-(4-((2-amino-3-(3-hydroxyl third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-4 methoxyl groups-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 50:1-(4-((2-amino-3-(3-dimethylamino third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 51:1-(4-((2-amino-3-(4-fluorophenyl) pyridin-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 52:1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl) the fluoro-phenyl of-N-(4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

The fluoro-4-(7-methoxyl group-6-(3-of compound 53:1-(3-morpholinyl-propoxy--quinazoline-4-yl) oxo-phenyl) the fluoro-benzyl of-N-(4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

The fluoro-4-(thiophene of compound 54:1-(3-[3,2-b] pyridin-7-yl) oxo-phenyl) the fluoro-benzyl of-N-(4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

The fluoro-4-(6-methoxyl group-7-(3-of compound 55:1-(3-morpholinyl-propoxy--quinolyl-4) oxo-phenyl) the fluoro-benzyl of-N-(4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 56:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-phenyl of-N-(4-)-2-oxo-1,2-dihydropyridine-3-acid amides

Compound 57:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-luorobenzyl) the fluoro-benzyl of-N-(4-)-2-oxo-1,2-dihydropyridine-3-acid amides

Compound 58:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-phenyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 59:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-phenyl of-N-(4-)-2-oxo-1,2-dihydropyridine-4-acid amides

Compound 60:1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl) the fluoro-benzyl of-N-(4-)-2-oxo-1,2-dihydropyridine-4-acid amides

The fluoro-4-(thiophene of compound 61:1-(3-[3,2-b] pyridin-7-yl) amino-phenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

The fluoro-4-(thiophene of compound 62:1-(3-[3,2-d] pyrimidine-4-yl) amino-phenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 63:1-(4-(6,7-dimethoxyquinazoline-4-yl) the fluoro-phenyl of amino 3-) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 64:1-(4-(6-benzyloxy-7-methoxyl group quinazoline-4-yl) the fluoro-phenyl of amino 3-) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

The fluoro-4-(7-methoxyl group-6-(3-of compound 65:1-(3-morpholinyl-propoxy--quinazoline-4-yl) amino-phenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

Compound 66:1-(3-fluoro-((7-methoxy quinoline-4-yl) amino-phenyl) the fluoro-benzyl of-N-(4-)-6-oxo-1,6-dihydropyridine-3-acid amides

As preferably, the present invention also provides a kind of structure suc as formula the compound shown in V or its pharmacy acceptable salt,

A is selected from following group:

As preferably, structure provided by the invention, suc as formula compound shown in V, is specially:

Compound 67:1-(4-((2-amide group-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-6-oxo-1,6-dihydropyridine-3-carboxylic acid

Compound 68:1-(4-((2-amide group-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-carboxylic acid

The present invention also provides the preparation method of a kind of structure suc as formula compound shown in V, and substrate is structure suc as formula compound shown in V A and structure suc as formula compound shown in V B,

Described substrate generating structure under the catalysis of DMAP, suc as formula the compound shown in V C, makes structure provided by the invention suc as formula compound shown in V through basic hydrolysis.

The present invention also provides structure suc as formula the compound shown in VI or its pharmacy acceptable salt:

Wherein: X is selected from C or N; R ¹be selected from hydrogen or halogen;

R ²be selected from hydrogen or OR ⁷; R ⁷be selected from hydrogen, alkyl, substituted alkyl, allyl group or substituted allyl; R ³be selected from hydroxyl, alkoxyl group ,-NR ¹⁰r ¹¹or-N (CH ₂) _p(R ¹²) (CH ₂) _pr ¹³; P is 0-2;

R ¹⁰and R ¹¹heterocyclic radical or R independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement ¹⁰and R ¹¹form altogether a heterocyclic radical;

R ¹²and R ¹³independently be selected from the heterocyclic radical of hydrogen, cyano group, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical or replacement.

As preferably, structure, suc as formula the compound shown in VI, is specially:

The fluoro-4-hydroxy phenyl of compound 69:1-(3-) the fluoro-benzyl-6-of-N-4-oxo-1,6-dihydropyridine-3-acid amides

The fluoro-4-hydroxy phenyl of compound 70:1-(3-)-N-4-fluoro-benzyl-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

The present invention also provides the preparation method of structure suc as formula compound shown in VI, substrate be structure suc as formula compound shown in XI,

Under the condition that described substrate exists at condensing agent with structure suc as formula the replacement amine generation substitution reaction shown in VI A, generating structure is suc as formula the compound shown in VI B, then under the catalysis of palladium-carbon, hydrogenating reduction makes structure provided by the invention suc as formula the compound shown in VI.

The present invention also provides structure suc as formula the compound shown in VII or its pharmacy acceptable salt,

Wherein, Y ¹be selected from hydrogen, aryl, heteroaryl or-(CH ₂) _ny ⁵; Y ²be selected from hydrogen, halogen; Y ³be selected from hydrogen, hydroxyl, OY ⁴; Y ⁴be selected from hydrogen, alkyl, alkoxyl group, allyl group; Y ⁵be selected from aryl, heteroaryl; N is 1; B is selected from O, NH.

The present invention also provides the preparation method of structure suc as formula compound shown in VII, and substrate is structure suc as formula compound shown in VII A and structure suc as formula compound shown in VII B,

Described substrate generating structure under the catalysis of DMAP, suc as formula the compound shown in VII C, then makes structure suc as formula the compound shown in VII through basic hydrolysis.

As preferably, the present invention also provides structure suc as formula the compound shown in VIII or its pharmacy acceptable salt,

Wherein, Y ¹be selected from hydrogen, aryl, heteroaryl or-(CH ₂) _ny ⁵; Y ²be selected from hydrogen, halogen; Y ⁴be selected from hydrogen, alkyl, alkoxyl group, allyl group; Y ⁵be selected from aryl, heteroaryl; N is 1; B is selected from O, NH.

The present invention also provides the preparation method of structure suc as formula compound shown in VIII, and substrate is structure suc as formula compound shown in VII A and structure suc as formula compound shown in VIII A,

Described substrate generating structure under the catalysis of DMAP, suc as formula the compound shown in VIII B, makes structure suc as formula the compound shown in VIII through basic hydrolysis.

The present invention also provides the preparation method of a kind of structure suc as formula compound shown in VIII, substrate be structure suc as formula compound shown in IV A,

Step 2: described structure refluxes and obtains structure suc as formula compound shown in VIII C suc as formula compound shown in compound shown in IV B and formula VII C in ethanol;

Step 3: described structure under the existence of acid binding agent, nucleophilic substitution occurs suc as formula compound shown in VIII C and halogenating agent, makes structure suc as formula compound shown in VIII D;

Step 4: described structure is hydrolyzed and obtains structure suc as formula the compound shown in VIII suc as formula compound shown in VIII D in aqueous sodium hydroxide solution.

The present invention also provides a kind of structure suc as formula the compound shown in IX,

Wherein, Y ⁶be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyano group ,-NY ⁹y ¹⁰, aryl, heteroaryl; Y ⁷be selected from hydrogen, hydroxyl, OY ¹¹or-NY ⁹y ¹⁰; Y ⁹and Y ¹⁰independently be selected from hydrogen, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl, heterolipid cyclic group, or Y ⁹and Y ¹⁰form altogether a heterocyclic radical; Y ¹¹be selected from hydrogen, alkyl, cycloalkyl, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Bn is benzyl.

The present invention also provides the preparation method of structure suc as formula compound shown in IX, and substrate is structure suc as formula compound shown in IX A and structure suc as formula compound shown in IX B,

Described substrate generating structure under the catalysis of DMAP, suc as formula the compound shown in IX C, makes structure suc as formula compound shown in IX through basic hydrolysis.

As preferably, the present invention also provides structure suc as formula the compound shown in X or its pharmacy acceptable salt,

Wherein, Y ⁶be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyano group ,-NY ⁹y ¹⁰, aryl, heteroaryl; Y ⁹and Y ¹⁰independently be selected from hydrogen, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl, heterolipid cyclic group, or Y ⁹and Y ¹⁰form altogether a heterocyclic radical; Y ¹¹be selected from hydrogen, alkyl, cycloalkyl, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Bn is benzyl.

The present invention also provides the preparation method of structure suc as formula compound shown in X, and substrate is structure suc as formula compound shown in X A and structure suc as formula compound shown in X B,

Described substrate generating structure under the catalysis of DMAP, suc as formula the compound shown in X C, makes structure suc as formula the compound shown in X through basic hydrolysis.

The present invention also provides the preparation method of structure suc as formula compound shown in X, substrate be structure suc as formula compound shown in IV A,

Step 2: described structure refluxes and obtains structure suc as formula compound shown in X D suc as formula compound shown in compound shown in IV B and formula IX A in ethanol;

Step 3: described structure under the existence of acid binding agent, nucleophilic substitution occurs suc as formula the halogenating agent shown in X E suc as formula compound shown in X D and structure, makes structure suc as formula compound shown in X F;

Step 4: described structure is hydrolyzed and obtains structure suc as formula the compound shown in X suc as formula compound shown in X F in aqueous sodium hydroxide solution.

The present invention also provides structure suc as formula the compound shown in XI or its pharmacy acceptable salt,

Wherein, X is selected from C or N; If X is C, n is 0-4; If X is N, n is 0-3;

M is 0-3; Bn is benzyl.

The present invention also provides the preparation method of structure suc as formula compound shown in XI, substrate be structure suc as formula compound shown in IV A,

Step 2: described structure refluxes in ethanol suc as formula compound shown in compound shown in IV B and formula XI A,

Wherein, Bn is benzyl, and the compound making and halogenating agent, under the existence of acid binding agent, nucleophilic substitution occurs, and the compound making is hydrolyzed and obtains structure suc as formula the compound shown in XI again in aqueous sodium hydroxide solution.

The present invention also provides structure suc as formula the compound shown in XII or its pharmacy acceptable salt,

Wherein, Y ¹be selected from hydrogen, aryl, heteroaryl or-(CH ₂) _ny ⁵; Y ²be selected from hydrogen, halogen; Y ³be selected from hydrogen, hydroxyl, OY ⁴; Y ⁴be selected from hydrogen, alkyl, alkoxyl group, allyl group; Y ⁵be selected from aryl, heteroaryl; N is 1; B is selected from O, NH;

R ¹⁰and R ¹¹independently be selected from heterocyclic radical, the aralkyl of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement, Heterocyclylalkyl or the R of the aralkyl of replacement, Heterocyclylalkyl, replacement ¹⁰and R ¹¹the heterocyclic radical forming.

The present invention also provides the preparation method of structure suc as formula compound shown in XII, and substrate is that structure provided by the invention is reacted suc as formula replacing amine shown in III D with structure suc as formula compound shown in VII, makes structure suc as formula the compound shown in XII.

As preferably, the present invention also provides structure suc as formula the compound shown in X III or its pharmacy acceptable salt,

Wherein, Y ¹be selected from hydrogen, aryl, heteroaryl or-(CH ₂) _ny ⁵; Y ²be selected from hydrogen, halogen; Y ⁴be selected from hydrogen, alkyl, alkoxyl group, allyl group; Y ⁵be selected from aryl, heteroaryl; N is 1; B is selected from O, NH;

The present invention also provides the preparation method of structure suc as formula compound shown in X III, and substrate structure reacts suc as formula replacing amine shown in III D with structure suc as formula compound shown in VIII, makes described compound.

The present invention also provides structure suc as formula the compound shown in X IV or its pharmacy acceptable salt,

Wherein, Y ⁶be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyano group ,-NY ⁹y ¹⁰, aryl, heteroaryl; Y ⁷be selected from hydrogen, hydroxyl, OY ¹¹or-NY ⁹y ¹⁰; Y ⁹and Y ¹⁰independently be selected from hydrogen, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl, heterolipid cyclic group, or Y ⁹and Y ¹⁰form altogether a heterocyclic radical; Y ¹¹be selected from hydrogen, alkyl, cycloalkyl, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Bn is benzyl R ¹⁰and R ¹¹independently be selected from heterocyclic radical, the aralkyl of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement, Heterocyclylalkyl or the R of the aralkyl of replacement, Heterocyclylalkyl, replacement ¹⁰and R ¹¹the heterocyclic radical forming.

The present invention also provides the preparation method of structure suc as formula compound shown in X IV, and substrate structure reacts suc as formula replacing amine shown in III D with structure suc as formula compound shown in IX, makes described compound.

The present invention also provides structure suc as formula the compound shown in X V or its pharmacy acceptable salt,

Wherein, Y ⁶be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyano group ,-NY ⁹y ¹⁰, aryl, heteroaryl; Y ⁹and Y ¹⁰independently be selected from hydrogen, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl, heterolipid cyclic group, or Y ⁹and Y ¹⁰form altogether a heterocyclic radical; Y ¹¹be selected from hydrogen, alkyl, cycloalkyl, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Bn is benzyl;

The present invention also provides the preparation method of structure suc as formula compound shown in X V, and substrate structure reacts suc as formula replacing amine shown in III D with structure suc as formula compound shown in X, makes described compound.

The present invention also provides structure suc as formula the compound shown in X VI or its pharmacy acceptable salt,

Wherein, Y ⁶be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyano group ,-NY ⁹y ¹⁰, aryl, heteroaryl; Y ⁷be selected from hydrogen, hydroxyl, OY ¹¹or-NY ⁹y ¹⁰; Y ⁸be selected from hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, heteroaryloxy, benzyloxy ,-N Y ⁹y ¹⁰,--N (CH ₂) _m(Y ¹²) (CH ₂) _my ¹³; Y ⁹and Y ¹⁰independently be selected from hydrogen, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl, heterolipid cyclic group, or Y ⁹and Y ¹⁰form altogether a heterocyclic radical; Y ¹¹be selected from hydrogen, alkyl, cycloalkyl, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Y ¹²and R ¹³independently be selected from hydrogen, cyano group, alkyl, aryl, heteroaryl; M is selected from 0,1,2 or 3.

The present invention also provides the preparation method of structure suc as formula compound shown in X VI, substrate be structure suc as formula compound shown in IX,

Under the condition that described substrate exists at condensing agent with structure suc as formula the replacement amine generation substitution reaction shown in X VI B, generating structure is suc as formula the compound shown in X VI C, then, under the catalysis of palladium-carbon, hydrogenating reduction makes described compound.

As preferably, the present invention also provides structure suc as formula the compound shown in X VII or its pharmacy acceptable salt,

Wherein, Y ⁶be selected from hydrogen, halogen, alkyl, hydroxyl, alkoxyl group, nitro, cyano group ,-NY ⁹y ¹⁰, aryl, heteroaryl; Y ⁸be selected from hydrogen, halogen, hydroxyl, alkoxyl group, aryloxy, heteroaryloxy, benzyloxy ,-N Y ⁹y ¹⁰,--N (CH ₂) _m(Y ¹²) (CH ₂) _my ¹³; Y ⁹and Y ¹⁰independently be selected from hydrogen, alkyl, alkoxyl group, cycloalkyl, aryl, heteroaryl, heterolipid cyclic group, or Y ⁹and Y ¹⁰form altogether a heterocyclic radical; Y ¹¹be selected from hydrogen, alkyl, cycloalkyl, alkoxyl group, allyl group, aryl, heteroaryl, heterolipid cyclic group; Y ¹²and R ¹³independently be selected from hydrogen, cyano group, alkyl, aryl, heteroaryl; M is selected from 0,1,2 or 3.

The present invention also provides the preparation method of structure suc as formula compound shown in X VII, substrate be structure suc as formula compound shown in X,

Under the condition that described substrate exists at condensing agent with structure suc as formula the replacement amine generation substitution reaction shown in X VII B, generating structure is suc as formula the compound shown in X VII C, then, under the catalysis of palladium-carbon, hydrogenating reduction makes described compound.

The present invention also provides structure suc as formula the compound shown in X VIII or its pharmacy acceptable salt,

A is selected from following group:

Wherein, R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰, R ²¹, R ²², R ²³, R ²⁴, R ²⁵, R ²⁶, R ²⁷, R ²⁸, R ²⁹, R ³⁰, R ³¹, R ³², R ³³, R ³⁴, R ³⁵, R ³⁶, R ³⁷, R ³⁸, R ³⁹, R ⁴⁰, R ⁴¹, R ⁴², R ⁴³, R ⁴⁴, R ⁴⁵, R ⁴⁶, R ⁴⁷, R ⁴⁸, R ⁴⁹, R ⁵⁰, R ⁵¹, R ⁵², R ⁵³, R ⁵⁴, R ⁵⁵, R ⁵⁶, R ⁵⁷, R ⁵⁸, R ⁵⁹, R ⁶⁰, R ⁶¹, R ⁶², R ⁶³, R ⁶⁴, R ⁶⁵, R ⁶⁶and R ⁶⁷independently be selected from is hydrogen, halogen, haloalkyl, nitro, cyano group, OR ⁶⁸, NR ⁶⁹r ⁷⁰, CO ₂r ⁷¹,-C (O) NR ⁷²r ⁷³, SO ₂r ⁷⁴, S (O) ₂nR ⁷⁵r ⁷⁶, NR ⁷⁷s (O) ₂r ⁷⁸, NR ⁷⁹c (O) R ⁸⁰, NR ⁸¹cO ₂r ⁸²,-CO (CH ₂) _rr ⁸³,-CONH (CH ₂) _rr ⁸⁴, SR ⁸⁵, SOR ⁸⁶, heterocyclic radical, the aralkyl of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, thiazolinyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement be, the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or the replacement of replacement; R is 0-4;

The present invention also provides the preparation method of structure suc as formula compound shown in X VIII, and substrate structure suc as formula the substituted heterocycle generation substitution reaction shown in formula IV D, makes described compound suc as formula the compound shown in X VI and structure.

The present invention also provides structure suc as formula the compound shown in X IX or its pharmacy acceptable salt,

A is selected from following group:

The present invention also provides the preparation method of structure suc as formula compound shown in X IX, and substrate structure suc as formula the substituted heterocycle generation substitution reaction shown in IV D, makes described compound suc as formula the compound shown in X and structure.

As preferably, described condensing agent comprises N, N'-dicyclohexylcarbodiimide, N, N'-DIC, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, 2-are chloro-4,6-dimethoxy-1,3,5-triazine, 2, the chloro-6-methoxyl group-1.3.5-of 4-bis-triazine, 1,1'-carbonyl dimidazoles and I-hydroxybenzotriazole, be preferably EDCI and HOBt.

As preferably, described acid binding agent comprises salt of wormwood, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium tert.-butoxide, sodium tert-butoxide, sodium methylate, sodium ethylate, triethylamine, diethyl Isopropylamine, is preferably potassium tert.-butoxide.

In reaction, the structure of acid binding agent itself is more stable, can not cause detrimentally affect to reactant and reaction solution, adds the acid that acid binding agent produces in can complex reaction, reduces the destruction of acid to product, and reaction forward is carried out, and improves yield.

As preferably, described temperature of reaction is 30-80 ℃, is preferably 25-50 ℃.

As preferably, the described reaction times is 5-16h, is preferably 8-12h.

Structure forms the combinatorial libraries with formula IV structural compounds suc as formula phenol fragment and the reaction of various substituted heterocycle of compound shown in VI.

Combinatorial libraries refers in the compound of multidimensional array by each compound of one dimension and reacts with the compound in other each dimension all compounds that form.In the context of the invention, described array is pyridonecarboxylic acid class or pyridone phenol fragment and all amine or the halogenated heterocyclics of two-dimensional representation the present invention two dimension and that one-dimensional representation the present invention is all.Each pyridonecarboxylic acid class or pyridone phenol fragment can react to form the pyridinone compounds suc as formula shown in I with each amine or halogenated heterocyclic.The all pyridinone compounds that form with the method are in the scope of the invention.

Wherein, X is selected from C or N; B is selected from O, S or NH; R ¹be selected from hydrogen or halogen; R ²be selected from hydrogen or OR ⁷; N is 0-2; M is 0-2;

R ⁷be selected from hydrogen, alkyl, substituted alkyl, allyl group or substituted allyl; R ³be selected from hydroxyl, alkoxyl group ,-NR ¹⁰r ¹¹or-N (CH ₂) _p(R ¹²) (CH ₂) _pr ¹³; P is 0-2;

R ¹⁰and R ¹¹independently be selected from heterocyclic radical or the R of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement ¹⁰and R ¹¹form altogether a heterocyclic radical;

A is selected from following figure:

R ¹⁶, R ¹⁷, R ¹⁸, R ²⁶, R ²⁷, R ²⁹, R ³⁰, R ³¹and R ³²independently be selected from hydrogen, halogen, nitro, cyano group, OR ⁶⁸, NR ⁶⁹r ⁷⁰, CO ₂r ⁷¹,-C (O) NR ⁷²r ⁷³, NR ⁷⁹c (O) R ⁸⁰, NR ⁸¹cO ₂r ⁸²,-CO (CH ₂) _rr ⁸³,-CONH (CH ₂) _rr ⁸⁴, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement heterocyclic radical;

R ⁶⁸, R ⁶⁹, R ⁷⁰, R ⁷¹, R ⁷², R ⁷³, R ⁷⁹, R ⁸⁰, R ⁸¹, R ⁸², R ⁸³, R ⁸⁴, R ⁸⁵and R ⁸⁶independently be selected from the heterocyclic radical of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement;

R is 0-4; Z is N or CR ⁸⁹;

R ⁸⁹independently be selected from the heterocyclic radical of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic radical, replacement.

The present invention also provides the isomer of above-mentioned each compound, pharmaceutically acceptable Equivalent or pharmacy acceptable salt.

The present invention also provides above-mentioned each compound in the application as Tyrosylprotein kinase and/or serine-threonine kinase inhibitor.

The present invention also provides the purposes of above-mentioned each compound in the medicine for the preparation for the treatment of Mammals or human protein kinase relative disease.

As preferably, described protein kinase related disorder is selected from relevant disease or the relevant disease of serine-threonine kinase of disease, nonreceptor tyrosine kinase that receptor tyrosine kinase is relevant.

As preferably, described protein kinase related disorder is selected from pHGF, relevant relevant relevant disease or the relevant disease of tire liver kinases of disease, IGF-1 of disease, platelet derived growth factor receptor of disease, EGF-R ELISA that vascular endothelial growth factor receptor is relevant.

As preferably, described protein kinase related disorder is selected from squamous cell carcinoma, stellate cell cancer, Kaposi's sarcoma, spongioblast cancer, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, mammary cancer, neurospongioma, colorectal carcinoma, liver cancer, kidney, genitourinary cancer, carcinoma of the pancreas or gastrointestinal cancer.

As preferably, described protein kinase related disorder is selected from diabetes, excess proliferative disease, blood vessel generation, inflammatory diseases, immunological disease or cardiovascular disorder.

The present invention also provides a kind of medicinal compositions that is used for the treatment of protein kinase related disorder in organism, comprises above-mentioned each compound provided by the invention and pharmaceutically acceptable carrier or vehicle.

Pharmacy acceptable salt represents to retain those salt of biological effectiveness and the character of parent compound.This class salt comprises: (1) and sour salify, free alkali by parent compound reacts and obtains with mineral acid or organic acid, mineral acid comprises hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc., organic acid comprises acetic acid, propionic acid, vinylformic acid, oxalic acid, (D) or (L) oxysuccinic acid, fumaric acid, toxilic acid, hydroxy-benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methylsulfonic acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, tosic acid, Whitfield's ointment, tartrate, citric acid, lactic acid, amygdalic acid, succsinic acid or propanedioic acid etc.(2) salt that is present in that acid proton in parent compound is replaced by metal ion or is generated with organic bases ligand compound, metal example is alkalimetal ion, alkaline-earth metal ions or aluminum ion for example, organic bases such as thanomin, diethanolamine, trolamine, Trometamol, N-METHYL-ALPHA-L-GLUCOSAMINE etc.

Medicinal compositions refers to one or more compounds or their pharmacy acceptable salt and prodrug and other chemical composition, comprises the mixture of pharmaceutically acceptable carrier and vehicle.The object of medicinal compositions is to promote the administration of compound to organism.

Pharmaceutically acceptable carrier refers to organism is not caused obvious pungency and do not disturb the biological activity of given compound and the carrier of character or thinner.

Vehicle refers to and joins in medicinal compositions with the further convenient inert substance that gives compound.Vehicle comprises calcium carbonate, calcium phosphate, various saccharides and polytype starch, derivatived cellulose, gelatin, vegetables oil and polyoxyethylene glycol.

Purposes in the medicine of the compounds of this invention protein kinase related disorder in for the preparation for the treatment of organism comprises: relevant disease or the relevant disease of serine-threonine kinase of disease, nonreceptor tyrosine kinase that the preferred autoreceptor Tyrosylprotein kinase of protein kinase related disorder is relevant; Described protein kinase related disorder or preferably from the relevant disease of vascular endothelial growth factor receptor, relevant relevant disease or the relevant disease of tire liver kinases of disease, IGF-1 of disease, platelet derived growth factor receptor that EGF-R ELISA is relevant; Described protein kinase related disorder or preferably from squamous cell carcinoma, stellate cell cancer, Kaposi's sarcoma, spongioblast cancer, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, mammary cancer, neurospongioma, colorectal carcinoma, liver cancer, kidney, genitourinary cancer, carcinoma of the pancreas or gastrointestinal cancer; Described protein kinase related disorder or preferably from diabetes, excess proliferative disease, blood vessel generation, inflammatory diseases, immunological disease or cardiovascular disorder; Described organism is Mammals or people; And a kind of medicinal compositions that is used for the treatment of protein kinase related disorder in organism, it comprises the compounds of this invention or salt and pharmaceutically acceptable carrier or vehicle.

In order to check compound provided by the invention for the exposure level of protein kinase, adopt the test of biochemistry level enzymic activity, the test of cell levels enzymic activity, inhibition tumor cell proliferation activity to test and determine that various compound of the present invention is to the activity of one or more PK and exposure level.The method of knowing in operation, all tests like design class in the same way for any kinases.

In the test of biochemistry level enzymic activity, utilize the activity of HTRF technology for detection Tyrosylprotein kinase, HTRF is a kind of time resolved fluorescence resonance ability transfer techniques, can carry out according to known specification sheets or literature method, referring to Kolb etc., " Tyrosine kinase assays adapted to homogenous time-resolved fluorescence " .Drug Discovery Today magazine .3 volume: pp333-342.HTRF (homogeneous phase time discrimination fluorescence) is for detecting a kind of the most frequently used method of determinand in homogeneous system, this technology combines FRET (fluorescence resonance energy transfer) (FRET) and TIME RESOLVED TECHNIQUE (TR), has been widely used in the different steps of the medicament research and development based on cell experiment and biochemical test.According to the measuring principle of HTRF method, by pure enzyme Met together with biotinylated substrate and ATP after incubation reaction, the antibody that adds the XL-665 of avidin mark and the Eu mark of identification substrate phosphorylation, after substrate is by Met phosphorylation, the antibody of Eu mark can identify this phosphorylation product, the FRET (fluorescence resonance energy transfer) (FRET) of differentiating with the XL665 formation time of avidin mark, and the substrate not being phosphorylated is due to can not times antibody recognition and cannot form FRET signal, by measure the fluorescent signal difference of 665nm and 620nm measure determinand under different concns to c-Met, Flt-3, VEGFR-2, PDGFR-β, the inhibition of the Tyrosylprotein kinases such as c-Kit is active.Thereby, adopt this method can measure the active function of the compounds of this invention to the biochemistry level of above-mentioned Tyrosylprotein kinase, utilize method well known in the art simultaneously, can use similar measuring method to other protein kinase.

In the test of cell levels enzymic activity, enzyme-linked immunosorbent assay (ELISA) can be used for checking and measuring the existence of tyrosine kinase activity.ELISA can carry out in accordance with known methods, such as Voller etc., 1980, " enzyme-linked immunosorbent assay " (Enzyme-Linkd Immunosorbent Assay), see the < < clinical immunology handbook > > (Manual of Clinical Immunology) that Rose and Friedman write, the 2nd edition, pp359-371, AAM publishes, Washington D.C..The phosphorylation reaction of the peptide substrate of the tyrosine-kinase enzyme catalysis ATP such as c-Met, Flt-3, VEGFR-2, PDGFR-β, c-Kit and vitamin H mark mark, inhibitory enzyme activity will suppress this reaction.According to ELISA method measuring principle, will resist Met antibody to be coated on solid phase carrier, capture the Met total protein in cell pyrolysis liquid; Then with the part of phosphorylation occurs in anti-tyrosine phosphorylation antibody labeling Met albumen; The antibody that adds horseradish peroxidase (HRP) mark, makes it and anti-tyrosine phosphorylation antibodies; The substrate TMB colour developing that finally adds HRP.By measuring the absorbancy at 450nmol/L absorbing wavelength place, detect Met acceptor autophosphorylation level in cell, thereby it is active to the inhibition of the Tyrosylprotein kinases such as c-Met, Flt-3, VEGFR-2, PDGFR-β, c-Kit under different concns to measure determinand.Thereby, adopt this method can measure the active function of the compounds of this invention to above-mentioned Tyrosylprotein kinase cell levels, utilize method well known in the art simultaneously, can use similar measuring method to other protein kinase.

In the test of inhibition tumor cell proliferation activity, measure and adopt routinely blue (MTT) method of bromination tetrazole.Succinodehydrogenase in viable cell plastosome can make the bromination 3-(4 of exogenous yellow, 5-dimethylthiazole-2)-2,5-phenylbenzene tetrazole (MTT) is reduced to the bluish voilet crystallisate Jia Za (Formazan) of insoluble, and be deposited in cell, and dead cell is without this function, purple crystal thing first Za in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measures its absorbance value with enzyme-linked immunosorbent assay instrument at 570nm wavelength place, can indirectly reflect viable cell quantity.Thereby first Za growing amount is directly proportional to viable count under normal conditions, can infer the number that viable cell according to OD value, understand that medicine suppresses or the ability of killer cell.This measuring method can utilize method well known in the art for measuring the inhibition ability of different the compounds of this invention to one or more cancer cell multiplications, can use similar measuring method to any cancer cells.

Structure prepared by the present invention has good restraining effect suc as formula the compound shown in I to multiple kinase activity, and it is to c-Met kinases half-inhibition concentration (IC ₅₀) generally 10 ^-6below mol/L.Meanwhile, the compound with formula I structure of preparing in the embodiment of the present invention is inhibited to the propagation of kinds of tumor cells, and wherein the effect of majority of compounds inhibition tumor cell propagation is remarkable, its IC ₅₀10 ^-5below mol/L.Have this to know by inference, the compound that the present invention has formula I structure can be applicable to the medicine that protein kinase related disorder in organism is treated in preparation.

Embodiment

The invention discloses intermediate of a kind of compound and preparation method thereof, this compound and preparation method thereof, and this compound is as the application of Tyrosylprotein kinase and/or serine-threonine kinase inhibitor, those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described or suitably change and combination within not departing from content of the present invention, spirit and scope, realizes and apply the technology of the present invention.

Below in conjunction with embodiment, further set forth the present invention:

Embodiment 1: prepare compound 67

Take the compound S 1 that 1.27g is about 10mmol, 1.71g is about the benzyl bromine of 10mmol, 1.38g is about the salt of wormwood of 10mmol, be placed in 250mL reaction flask, add 100mL DMF, stirred overnight at room temperature, concentrate to obtain yellow solid, with petroleum ether-ethyl acetate, according to the gradient of 0-25%, carry out wash-out, obtain 1.85g yellow oily compound S 2, productive rate 85%.

Take the compound S 2 that 1.09g is about 5mmol, 0.77g is about the compound S 3 of 5mmol, the DMAP that 0.61g is about 5mmol is placed in 250mL reaction flask, add 100mL ethanol, 90 ℃ of stirring reaction 2h, concentrate to obtain yellow solid, with petroleum ether-ethyl acetate, according to 0%～45% Russia's gradient, carry out wash-out, obtain 1.41g yellow solid compound S 4, productive rate 80%.

Take the compound S 4 that 1.41g is about 4mmol, 0.42g is about the Pd-C of 4mmol, in atmosphere of hydrogen, stirring at room, reaction is spent the night, and concentrates to obtain yellow solid, with petroleum ether-ethyl acetate, according to 0%～50% gradient, carry out wash-out, obtain 0.95 yellow solid compound S 5, productive rate 90%.

Take the compound S 5 that 0.79g is about 3mmol, 0.57g is about 3 of 3mmol, 4-dichloro-2-pyridyl acid amides, 0.34g is about the potassium tert.-butoxide of 3mmol, is placed in 100mL reaction flask, add 40mLDMF, stirred overnight at room temperature, the concentrated yellow solid that to obtain, with methyl alcohol-methylene dichloride according to 0%～5% gradient elution, obtain 1.06g yellow solid compound s 6, productive rate 85%.

Take the compound s 6 that 0.84g is about 2mmol, 0.08g is about the sodium hydroxide of 2mmol, water 20mL, 90 ℃ of stirring reaction 5h, are neutralized to 7 with the HCl of 3mol/L by reacting liquid pH value, suction filtration, be dried to obtain 0.72g yellow solid compound, compound 67, productive rate 89%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):12.1(s,1H),8.43(d,1H),7.88(m,2H),7.76(s,1H),7.68(m,2H),6.96(d,1H),6.64(d,1H)。

MS(ESI):403.8[M+H] ⁺。

Embodiment 2: prepare compound 68

Take the compound S 7 that 1.74g is about 10mmol, 1.19g is about the DMF-DMA of 10mmol, be placed in 250mL reaction flask, add 100mL DMF, 90 ℃ of stirring reaction 2h, concentrate and to obtain yellow solid, use petroleum ether-ethyl acetate according to the gradient elution of 0-15%, obtain 2.06g yellow solid compound S 8, productive rate 90%.

Take the compound S 8 that 2.06g is about 9mmol, 1.95g is about the compound S 2 of 9mmol, 1.10g is about the DMAP of 9mmol, be placed in 250mL reaction flask, add 100mL ethanol, 90 ℃ of stirring reaction 2h, concentrate to obtain yellow solid, with petroleum ether-ethyl acetate, according to the gradient elution of 0-45%, obtain 2.82g yellow solid compound S 9, productive rate 85%.

Take the compound S 9 that 1.84g is about 5mmol, 1.42g is about the methyl iodide of 10mmol, 0.69g is about the salt of wormwood of 5mmol, be placed in 250mL reaction flask, add 100mL acetonitrile, 80 ℃ of stirring reaction 2h, concentrate to obtain yellow solid, with petroleum ether-ethyl acetate, according to 0%～25% gradient elution, obtain 1.65g yellow solid compound S 10, productive rate 86%.

Take the compound S 10 that 1.53g is about 4mmol, 0.42g is about the Pd-C of 4mmol, in atmosphere of hydrogen, stirring at room, reaction is spent the night, and concentrates to obtain yellow solid, with petroleum ether-ethyl acetate, according to 0%～50% gradient elution, obtain 1.05 yellow solid compound Ss 11, productive rate 89%.

Take the compound S 11 that 0.88g is about 3mmol, 0.57g is about 3 of 3mmol, 4-dichloro-2-pyridyl acid amides, the potassium tert.-butoxide that 0.34g is about 3mmol is placed in 100mL reaction flask, adds 40mLDMF, stirred overnight at room temperature, concentrate to obtain yellow solid, with methyl alcohol-methylene dichloride, according to 0%～5% gradient elution, obtain 1.04g yellow solid compound S 12, productive rate 78%.

Take the compound S 12 that 0.89g is about 2mmol, 0.08g is about the sodium hydroxide of 2mmol, water 20mL, and 90 ℃ of stirring reaction 5h, are neutralized to pH=7 with 3mol/L HCl, and suction filtration is dried to obtain 0.80g yellow solid compound, and compound 68, productive rate 92%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):12.5(s,1H),8.48(d,1H),8.32(s,1H),8.07(d,1H),7.78(s,2H),7.56(m,1H),7.45(d,1H),6.96(s,1H),1.32(s,1H)。

MS(ESI):443.8[M+H] ⁺。

Embodiment 3: prepare compound 69

Take 1.77 compound Ss 4 that are about 5mmol, 0.2g is about the sodium hydroxide of 5mmol, water 50mL, and 90 ℃ of stirring reaction 5h, are neutralized to pH=7 with 3mol/L HCl, suction filtration, dry 1.53g yellow solid compound S 13, the productive rate 90% of obtaining.

Take 1.36 compound Ss 13 that are about 4mmol, 0.81mg is about the EDCI of 4mmol, 0.55g is about the HOBt of 4mmol, and 0.2g is about the DMAP of 1.64mmol, and the NSC 158269 that 0.5g is about 4mmol is placed in 250mL reaction flask, add 50mL DMF and 50mL methylene dichloride, stirred overnight at room temperature, the concentrated yellow solid that to obtain, with methyl alcohol-methylene dichloride according to 0%～5% gradient elution, obtain 1.07g yellow solid compound S 14, productive rate 75%.

Take the compound S 14 that 0.89g is about 2mmol, 0.21g is about the Pd-C of 2mmol, in atmosphere of hydrogen, stirring at room reaction is spent the night, the concentrated yellow solid that to obtain, with petroleum ether-ethyl acetate according to 0%～50% gradient elution, obtain 0.64g yellow solid compound, compound 69, productive rate 89%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.84(s,1H),8.34(dd,1H),7.83(d,1H),7.75(d,1H),7.43(m,2H),7.36(m,3H),6.57(t,1H),6.05(d,1H),5.85（s,1H），4.34(d,2H)。

MS(ESI):356.1[M+H] ⁺。

Embodiment 4: prepare compound 70

Take 1.92 compound Ss 10 that are about 5mmol, 0.2g is about the sodium hydroxide of 5mmol, water 50mL, and 90 ℃ of stirring reaction 5h, are neutralized to pH=7 with 3mol/L HCl, suction filtration, dry 1.70g yellow solid compound S 15, the productive rate 92% of obtaining.

Take 1.48 compound Ss 15 that are about 4mmol, 0.81mg is about the EDCI of 4mmol, and 0.55g is about the HOBt of 4mmol, and 0.2g is about the DMAP of 1.64mmol, 0.5g is about the NSC 158269 of 4mmol, be placed in 250mL reaction flask, add 50mL DMF and 50mL methylene dichloride, stirred overnight at room temperature, concentrate to obtain yellow solid, with methyl alcohol-methylene dichloride, according to 0%～5% gradient elution, obtain 1.52g yellow solid compound S 16, productive rate 80%.

Take the compound S 14 that 0.95g is about 2mmol, 0.21g is about the Pd-C of 2mmol, in atmosphere of hydrogen, and stirring at room, reaction is spent the night, and concentrates and to obtain yellow solid, uses petroleum ether-ethyl acetate according to 0%～50% Russia's gradient elution, obtain 0.73 yellow solid compound, compound 70, productive rate 95%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.80(s,1H),8.34(dd,1H),7.83(d,1H),7.72(d,1H),7.40(m,2H),7.34(m,3H),6.52(t,1H),5.75（s,1H），4.34(d,2H)，4.24（s，3H）。

MS(ESI):386.1[M+H] ⁺。

Embodiment 5: prepare compound 1

Take the compound 67 that 450mg is about 1.12mmol, 400mg is about the EDCI of 2.09mmol, and 280mg is about the HOBt of 2.09mmol, and 100mg is about the DMAP of 0.82mmol, 130mg is about the NSC 158269 of 1.04mmol, be placed in 250mL reaction flask, add 50mL DMF and 50mL methylene dichloride, stirred overnight at room temperature, concentrate to obtain yellow solid, with methyl alcohol-methylene dichloride, according to 0%～5% gradient elution, obtain 300mg yellow solid, productive rate 57%.

The yellow solid making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.86(s,1H),8.42(m,2H),8.35(m,3H),7.97(m,2H),7.84(m,1H),7.62(m,1H),7.35(m,3H),7.18(d,1H,J=9.0),6.94(t,1H),4.43(d,2H)。

MS(ESI):533[M+Na] ⁺,509[M-H] ^-。

Take 300mg and be about the above-mentioned yellow solid of 0.59mmol, be dissolved in 50mL ethyl acetate, 50mL acetonitrile and 25mL water, be cooled to 0 ℃, add 228mg to be about the iodobenzene diacetate of 0.7mmol, be warming up to 25 ℃, reaction 1h.Concentrated, with methyl alcohol-methylene dichloride, according to 0%～3% gradient elution, obtain 200mg white-yellowish solid, compound 1, productive rate 71%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.84(s,1H),8.34(dd,1H),7.97(dd,1H),7.83(d,1H),7.75(d,1H),7.43(m,2H),7.36(m,4H),6.57(t,1H),6.48(s,2H),6.05(d,1H),4.42(d,2H)。

MS(ESI):482.7[M+H] ⁺。

Embodiment 6: prepare compound 2

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 144mg yellow solid, compound 2, productive rate 27%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.85(m,1H),8.38(s,1H),8.02(d,1H),7.82(d,1H),7.74(d,1H),7.45(m,2H),7.36(m,1H),7.10-7.20(m,3H),6.57(t,1H),6.47(s,2H),6.05(d,1H),4.46(d,2H)。

MS(ESI):482.7[M+H] ⁺。

Embodiment 7: prepare compound 3

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 212mg yellow solid, compound 3, productive rate 36%.

The product making is tested, and result is as follows:

MS(ESI):532.1[M+H] ⁺。

Embodiment 8: prepare compound 4

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 203mg yellow solid, compound 4, productive rate 36%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.85(s,1H),8.34(dd,1H),7.97(dd,1H),7.82(d,1H),7.73(d,1H),7.40(m,2H),7.35(m,4H),6.57(t,1H),6.46(s,2H),6.07(d,1H),4.43(d,2H)。

MS(ESI):498.1[M+H] ⁺。

Embodiment 9: prepare compound 5

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 182mg yellow solid, compound 5, productive rate 38%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.79(s,1H),8.36(dd,1H),7.97(dd,1H),7.82(d,1H),7.73(d,1H),7.36(m,2H),7.17(m,4H),6.57(t,1H),6.46(s,2H),6.05(d,1H),4.47(d,2H)。

MS(ESI):482.7[M+H] ⁺。

Embodiment 10: prepare compound 6

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 130mg yellow solid, compound 6, productive rate 24%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.74(s,1H),8.33(dd,1H),7.97(dd,1H),7.82(d,1H),7.72(d,1H),7.43(m,2H),7.23(d,2H),6.89(m,2H),6.58(t,1H),6.46(s,2H),6.04(d,1H),4.37(d,2H)，3.72(s,3H)。

MS(ESI):494.1[M+H] ⁺。

Embodiment 11: prepare compound 7

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 304mg yellow solid, compound 7, productive rate 55%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.89(s,1H),8.36(dd,1H),7.96(dd,1H),7.82(d,1H),7.73(m,2H),7.35(m,6H),6.89(m,2H),6.53(t,1H),6.46(s,2H),6.05(d,1H),4.44(d,2H)。

MS(ESI):498.1[M+H] ⁺。

Embodiment 12: prepare compound 8

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 119mg yellow solid, compound 8, productive rate 22%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.93(s,1H),8.36(dd,1H),7.97(dd,1H),7.80(m,4H),7.50(m,4H),6.58(t,1H),6.23(s,2H),5.86(d,1H),4.51(d,2H)。

MS(ESI):489.1[M+H] ⁺。

Embodiment 13: prepare compound 9

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 174mg yellow solid, compound 9, productive rate 35%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.82(s,1H),8.36(dd,1H),7.97(dd,1H),7.82(d,1H),7.75(d,1H),7.32(m,2H),7.26(m,4H),6.57(t,1H),6.47(s,2H),6.04(d,1H),4.45(d,2H)。

MS(ESI):446.1[M+H] ⁺。

Embodiment 14: prepare compound 10

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 223mg yellow solid, compound 10, productive rate 37%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.97(s,1H),8.36(dd,1H),7.96(dd,1H),7.83(d,1H),7.75(d,1H),7.59(m,4H),7.44(m,2H),6.59(t,1H),6.48(s,2H),6.06(d,1H),4.52(d,2H)。

MS(ESI):532.1[M+H] ⁺。

Embodiment 15: prepare compound 11

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 199mg yellow solid, compound 11, productive rate 33%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.92(s,1H),8.40(dd,1H),7.97(dd,1H),7.81(d,1H),7.76(d,1H),7.68(m,3H),7.44(m,3H),6.58(t,1H),6.46(s,2H),6.05(d,1H),4.62(d,2H)。

MS(ESI):532.1[M+H] ⁺。

Embodiment 16: prepare compound 12

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 135mg yellow solid, compound 12, productive rate 25%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.65(s,1H),8.36(dd,1H),7.97(dd,1H),7.82(d,1H),7.74(d,1H),7.45(m,2H),7.25(m,2H),6.92(m,2H),6.57(t,1H),6.46(s,2H),6.05(d,1H),4.41(d,2H)，3.81(s,3H)。

MS(ESI):494.1[M+H] ⁺。

Embodiment 17: prepare compound 13

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 222mg yellow solid, compound 13, productive rate 42%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.66(s,1H),8.38(dd,1H),7.95(dd,1H),7.82(d,1H),7.72(d,1H),7.46(m,2H),7.25(m,1H),7.14(m,3H),6.58(t,1H),6.45(s,2H),6.06(d,1H),4.42(d,2H)，2.30(s,3H)。

MS(ESI):478.1[M+H] ⁺。

Embodiment 18: prepare compound 14

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 298mg yellow solid, compound 14, productive rate 54%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.89(s,1H),8.50(dd,1H),7.97(dd,1H),7.70(m,3H),7.26(m,6H),6.55(t,1H),6.43(s,2H),6.07(d,1H),4.52(d,2H)。

MS(ESI):498.1[M+H] ⁺。

Embodiment 19: prepare compound 15

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 217mg yellow solid, be i.e. compound 16 productive rates 41%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):11.9(s,1H),8.80(s,1H),8.38(dd,1H),7.95(dd,1H),7.80(d,1H),7.46(m,4H),7.14(m,3H),6.55(t,1H),6.43(s,2H),6.05(d,1H),4.38(d,2H)，2.35(s,3H)。

MS(ESI):478.1[M+H] ⁺。

Embodiment 20: prepare compound 16

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 223mg yellow solid, compound 16, productive rate 37%.

The product making is tested, and result is as follows:

MS(ESI):532.1[M+H] ⁺。

Embodiment 21: prepare compound 17

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 136mg yellow solid, compound 17, productive rate 23%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.82(s,1H),8.32(dd,1H),7.96(dd,1H),7.85(d,1H),7.55(m,2H),7.45(m,2H),7.24(m,2H),7.15(m,2H),6.57(t,1H),6.45(s,2H),6.25(d,1H),6.12(m,2H),5.85(d,1H),4.45(d,2H)。

MS(ESI):464.1[M+H] ⁺。

Embodiment 22: prepare compound 18

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 207mg yellow solid, compound 18, productive rate 43%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.28(m,1H),7.95(d,1H),7.82(d,1H),7.60(d,1H),7.45(m,2H),6.55(m,3H),6.03(d,1H),3.02(t,2H)，1.75(m,1H)，0.85(d,6H)。

MS(ESI):430.1[M+H] ⁺。

Embodiment 23: prepare compound 19

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 140mg yellow solid, compound 19, productive rate 29%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.32(m,1H),7.95(d,1H),7.85(d,1H),7.75(d,1H),7.65(d,1H),7.38(m,2H),6.52(m,3H),6.05(d,1H),4.02(m,1H)，1.35(d,9H)。

MS(ESI):430.1[M+H] ⁺。

Embodiment 24: prepare compound 20

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 114mg yellow solid, compound 20, productive rate 24%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):12.45（b，1H），8.30(m,1H),7.96(d,1H),7.82(d,1H),7.74(d,1H),7.60(d,1H),7.45(m,2H),6.55(m,3H),6.03(d,1H),4.02(m,1H),1.18(d,9H)。

MS(ESI):416.8[M+H] ⁺。

Embodiment 25: prepare compound 21

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 172mg yellow solid, compound 21, productive rate 36%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.80（d，1H），8.35(d,1H),7.92(d,1H),7.85(d,1H),7.74(d,1H),7.70(d,1H),7.45(m,2H),6.60(d,1H),6.45(s,2H),6.03(m,1H),3.50(m,2H),2.75(t,2H)。

MS(ESI):427.1[M+H] ⁺。

Embodiment 26: prepare compound 22

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 102mg yellow solid, compound 22, productive rate 22%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):9.10（d，1H），8.39(d,1H),7.91(d,1H),7.80(m,2H),7.70(d,1H),7.49(m,2H),6.60(d,1H),6.50(s,2H),6.30(d,1H),6.13(m,2H),5.90(d,1H),4.35(d,2H)。

MS(ESI):413.1[M+H] ⁺。

Embodiment 27: prepare compound 23

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 142mg yellow solid, compound 23, productive rate 24%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):7.96(dd,1H),7.81(d,1H),7.65(m,2H),7.43(m,4H),7.20(m,2H),6.62(t,1H),6.48(s,2H),6.05(d,1H),4.75(s,2H)，4.45(s,2H)。

MS(ESI):521.1[M+H] ⁺。

Embodiment 28: prepare compound 24

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 173mg yellow solid, compound 24, productive rate 32%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):7.82(m,2H),7.74(d,1H),7.58(d,1H),7.23(m,6H),6.68(d,2H),6.15(m,1H),5.52(s,2H),3.85(s,2H)，3.00(t,2H)，1.25(t,2H)。

MS(ESI):490.1[M+H] ⁺。

Embodiment 29: prepare compound 25

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 230mg yellow solid, compound 25, productive rate 45%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.70(s,1H),8.39(dd,1H),7.95(dd,1H),7.82(d,1H),7.75(d,1H),7.55(m,1H),7.45(m,2H),6.59(d,1H),6.50(s,2H),6.36(d,1H),6.30(d,1H),6.05(d,1H),4.42(d,2H)。

MS(ESI):454.8[M+H] ⁺。

Embodiment 30: prepare compound 26

Take the compound 68 that 356mg is about 1.0mmol, 282mg is about the iodo-2-picolinamide of the chloro-3-of 4-of 1.0mmol, 112mg is about the potassium tert.-butoxide of 1.0mmol, be placed in 100mL reaction flask, add 40mL DMF, stirred overnight at room temperature, concentrate to obtain yellow solid, with methyl alcohol-methylene dichloride, according to 0%～5% gradient elution, obtain 373mg yellow solid, productive rate 62%.

Take the above-mentioned yellow solid that 300mg is about 0.50mmol, be dissolved in 50mL ethyl acetate, 50mL acetonitrile and 25mL water, be cooled to 0 ℃, add 228mg to be about 0.7mmol and starve iodobenzene diacetate, be warming up to 25 ℃, reaction 1h.Concentrated, with methyl alcohol-methylene dichloride, according to 0%～3% gradient elution, obtain 205mg yellow solid, that is, and compound 26, productive rate 71%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.85(m,1H),8.35(s,1H),7.95(d,1H),7.78(d,1H),7.75(d,1H),7.36(m,4H),7.15(m,2H),6.55(d,1H),6.25(s,2H),5.90(d,1H),4.42(d,2H)。

MS(ESI):574.0[M+H] ⁺。

Embodiment 31: prepare compound 27

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 291mg yellow solid, compound 27, productive rate 55%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.82(t,1H),8.34(d,1H),7.97(d,1H),7.85(d,1H),7.74(d,1H),7.36(m,4H),7.15(t,2H),6.65(d,1H),6.35(s,2H),5.93（d，1H），4.42(d,2H)。

MS(ESI):472.1[M+H] ⁺。

Embodiment 32: prepare compound 28

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 264mg yellow solid, compound 28, productive rate 47%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.83(t,1H),8.34(d,1H),7.96(d,1H),7.83(d,1H),7.70(d,1H),7.41(m,4H),7.15(t,2H),6.58(d,1H),6.37(s,2H),5.91（d，1H），5.25（t，1H）4.42(d,2H)，4.35(d,2H)。

MS(ESI):502.1[M+H] ⁺。

Embodiment 33: prepare compound 29

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 249mg yellow solid, compound 29, productive rate 42%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.86(t,1H),8.28(d,1H),7.94(d,1H),7.83(d,1H),7.65(d,1H),7.35(m,4H),7.10(t,2H),6.58(d,1H),6.52(d,1H),6.05（d，1H），4.40(d,2H)，3.50(s,2H)，2.20（s，6H）。

MS(ESI):529.2[M+H] ⁺。

Embodiment 34: prepare compound 30

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 296mg yellow solid, compound 30, productive rate 56%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):11.85(s,1H),8.78(t,1H),8.38(d,1H),8.15(d,1H),7.94(d,1H),7.75(d,1H),7.35(m,4H),7.15(t,2H),6.57(d,1H),6.45(d,1H),6.30（d，1H），4.42(d,2H)。

MS(ESI):472.1[M+H] ⁺。

Embodiment 35: prepare compound 31

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 349mg yellow solid, compound 31, productive rate 62%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):11.80(b,1H),8.90(t,1H),8.36(d,1H),8.08(d,1H),7.95(d,1H),7.75(d,1H),7.40(m,4H),7.15(m,3H),6.56(d,1H),6.45(d,1H),6.15（d，1H），5.55(b,1H)，4.55(d,2H)，4.42(d,2H)。

MS(ESI):502.2[M+H] ⁺。

Embodiment 36: prepare compound 32

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 237mg yellow solid, compound 32, productive rate 40%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):11.82(b,1H),8.92(t,1H),8.32(d,1H),8.05(d,1H),7.93(d,1H),7.65(d,1H),7.40(m,4H),7.16(t,2H),6.58(d,1H),6.42(d,1H),6.15（d，1H），4.45(d,2H)，3.55(s,2H)，2.20（s，6H）。

MS(ESI):529.2[M+H] ⁺。

Embodiment 37: prepare compound 33

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 320mg yellow solid, compound 33, productive rate 50%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):11.80(b,1H),8.90(t,1H),8.35(d,1H),8.04(d,1H),7.95(d,1H),7.75(d,1H),7.40(m,4H),7.14(t,2H),6.58(d,1H),6.45(d,1H),6.20（d，1H），4.40(d,2H)，3.65(t,4H)，2.58（t，4H）。

MS(ESI):571.2[M+H] ⁺。

Embodiment 38: prepare compound 34

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 331mg yellow solid, compound 34, productive rate 52%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):11.75(b,1H),9.20(t,1H),8.40(d,1H),8.02(d,1H),7.99(d,1H),7.75(d,1H),7.42(m,4H),7.12(t,2H),6.56(d,1H),6.40(d,1H),6.16（d，1H），4.40(d,2H)，3.55(m,2H)，3.35(m,4H)，2.58（m，4H）。

MS(ESI):569.2[M+H] ⁺。

Embodiment 39: prepare compound 35

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 357mg yellow solid I-35, productive rate 65%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):10.30(s,1H),8.84(m,2H),8.65(d,1H),8.45(d,1H),8.30(d,1H),7.95(m,2H),7.75(t,2H),7.55(d,1H),7.35(m,4H),7.15(m,6H),6.65(d,1H),6.50(d,2H),4.50(d,2H)。

MS(ESI):490.1[M+H] ⁺。

Embodiment 40: prepare compound 36

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 372mg yellow solid I-36, productive rate 68%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.85(t,1H),8.60(d,1H),8.35(d,1H),8.22(d,1H),8.00(d,1H),7.85(d,1H),7.68(m,2H),7.49(m,1H),7.35(m,2H),7.15(t,2H),6.75(d,1H),6.55(d,2H),4.40(d,2H)。

MS(ESI):489.1[M+H] ⁺。

Embodiment 41: prepare compound 37

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 366mg yellow solid, compound 37, productive rate 60%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.89(t,1H),8.56(d,1H),8.38(d,1H),8.00(d,1H),7.75(m,3H),7.60(s,1H),7.49(m,2H),7.35(m,2H),7.15(m,2H),6.50(d,1H),4.50(d,2H)，4.00(s,6H)。

MS(ESI):545.2[M+H] ⁺。

Embodiment 42: prepare compound 38

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 403mg yellow solid, compound 38, productive rate 58%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.60(d,1H),8.18(m,1H),7.72(m,2H),7.65(s,1H),7.45(m,10H),7.08(t,2H),6.65(d,1H),6.15(t,1H),5.30(d,2H)，4.60(d,2H)，4.05(s,3H)。

MS(ESI):620.2[M+H] ⁺。

Embodiment 43: prepare compound 39

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 515mg yellow solid, compound 39, productive rate 70%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.86(t,1H),8.60(d,1H),8.45(d,1H),8.00(d,1H),7.75(m,2H),7.60(s,1H),7.50(d,1H),7.45(s,1H),7.35(m,2H),7.16(t,2H),6.55(d,1H),4.60(d,2H)，4.25(t,2H)，4.05(s,3H)，3.60(t,4H)，2.52(m,2H)，2.45(m,4H)，2.00(m,2H)。

MS(ESI):657.2[M+H] ⁺。

Embodiment 44: prepare compound 40

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 339mg yellow solid, compound 40, productive rate 65%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.80(t,1H),8.60(s,1H),8.50(s,1H),8.00(dd,1H),7.83(m,2H),7.75(d,1H),7.43(m,2H),7.35(t,2H),7.15(t,2H),6.58(t,1H),6.50(s,2H),6.15(d,1H),4.42(d,2H)。

MS(ESI):465.1[M+H] ⁺。

Embodiment 45: prepare compound 41

Take the compound 68 that 485mg is about 1.12mmol, 400mg is about the EDCI of 2.09mmol, and 280mg is about the HOBt of 2.09mmol, and 100mg is about the DMAP of 0.82mmol, 130mg is about the NSC 158269 of 1.04mmol, be placed in 250mL reaction flask, add 50mL DMF and 50mL methylene dichloride, stirred overnight at room temperature, concentrate to obtain yellow solid, with methyl alcohol-methylene dichloride, according to 0%～5% gradient elution, obtain 393mg yellow solid, productive rate 65%.

Take the above-mentioned yellow solid that 319mg is about 0.59mmol, be dissolved in 50mL ethyl acetate, 50mL acetonitrile and 25mL water, be cooled to 0 ℃, add 228mg to be about the iodobenzene diacetate of 0.7mmol, be warming up to 25 ℃, reaction 1h.Concentrated, with methyl alcohol-methylene dichloride, according to 0%～3% gradient elution, obtain 241mg white-yellowish solid, compound 41, productive rate 80%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.52(t,1H),8.11(d,1H),,7.80(d,1H),7.65(d,1H),7.35(m,4H),7.15(t,2H),6.57(t,1H),6.45(s,2H),6.08(s,1H),6.00(d,1H),4.48(d,2H)，3.95(s,3H)。

MS(ESI):512.1[M+H] ⁺。

Embodiment 46: prepare compound 42

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 343mg yellow solid, compound 42, productive rate 62%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.50(t,1H),8.05(d,1H),7.85(d,1H),7.49(d,2H),7.35(m,2H),7.20(m,2H),7.15(t,2H),6.57(t,1H),6.40(s,2H),6.12(s,1H),6.00(d,1H),4.45(d,2H)，3.95(s,3H)。

MS(ESI):494.1[M+H] ⁺。

Embodiment 47: prepare compound 43

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 343mg yellow solid, compound 43, productive rate 62%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.39(t,1H),8.12(d,1H),7.80(d,1H),7.65(d,1H),7.38(m,4H),7.14(t,2H),6.57(t,1H),6.42(s,2H),6.08(s,1H),6.00(d,1H),4.45(d,2H)，4.18(t,2H)，1.45(q,3H)。

MS(ESI):526.1[M+H] ⁺。

Embodiment 48: prepare compound 44

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 349mg yellow solid, compound 44, productive rate 58%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.45(t,1H),8.10(d,1H),7.85(d,1H),7.65(d,1H),7.40(m,4H),7.14(t,2H),6.57(t,1H),6.52(s,2H),6.08(m,2H),6.00(d,1H),5.40(m,2H),4.76(m,2H)，4.45(m,2H)。

MS(ESI):538.1[M+H] ⁺。

Embodiment 49: prepare compound 45

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 386mg yellow solid, compound 45, productive rate 62%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.41(t,1H),8.02(d,1H),7.80(d,1H),7.35(m,4H),7.08(t,2H),6.18(d,1H),5.98(d,1H),5.50(b,2H)，4.56(d,2H)，4.20(t,2H)，3.70(t,2H)，3.18(d,3H)。

MS(ESI):556.1[M+H] ⁺。

Embodiment 50: prepare compound 46

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 352mg yellow solid, compound 46, productive rate 55%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.55(t,1H),8.16(d,1H),7.85(d,1H),7.65(d,1H),7.35(m,4H),7.15(m,2H),7.08(t,2H),6.45(m,2H),6.18(d,1H),5.98(d,1H),5.25(d,1H)，4.85(t,2H)，4.45(t,2H)，4.18(t,2H)，3.85(m,2H)，3.48(m,2H)。

MS(ESI):572.1[M+H] ⁺。

Embodiment 51: prepare compound 47

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 352mg yellow solid, compound 47, productive rate 55%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.52(t,1H),8.11(d,1H),7.76(d,1H),7.65(d,1H),7.35(m,4H),7.15(m,2H),6.25(s,2H),6.05(s,1H),5.95(d,1H),4.45(d,2H)，3.95(s,3H)。

MS(ESI):604.0[M+H] ⁺。

Embodiment 52: prepare compound 48

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 435mg yellow solid, compound 48, productive rate 60%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.41(t,1H),8.02(d,1H),7.82(d,1H),7.30(m,4H),7.06(t,2H),6.02(d,1H),5.95(d,1H),5.50(b,2H)，4.58(d,2H)，4.20(t,2H)，3.66(t,2H)，3.15(d,3H)。

MS(ESI):648.1[M+H] ⁺。

Embodiment 53: prepare compound 49

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 393mg yellow solid, compound 49, productive rate 66%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.52(t,1H),8.12(d,1H),7.80(d,1H),7.65(d,1H),7.36(m,4H),7.15(t,2H),6.58(d,1H),6.35(s,2H),6.04(d,1H),5.92（d，1H），5.25（t，1H）4.42(d,2H)，4.35(d,2H)，3.95(s,3H)。

MS(ESI):532.1[M+H] ⁺。

Embodiment 54: prepare compound 50

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 344mg yellow solid, compound 50, productive rate 55%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.56(t,1H),8.10(d,1H),7.85(d,1H),7.65(d,1H),7.35(m,4H),7.15(t,2H),6.25(s,2H),6.06(d,1H),6.00（d，1H），4.45(d,2H)，4.10(t,2H)，3.50(s,3H)，2.20（s，6H）。

MS(ESI):559.2[M+H] ⁺。

Embodiment 55: prepare compound 51

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 384mg yellow solid, compound 51, productive rate 60%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.55(t,1H),8.30(t,1H),8.15(m,2H),7.75(d,1H),7.65(d,1H),7.35(m,4H),7.15(m,3H),6.55(s,2H),6.08(s,1H),6.02(d,1H),4.46(d,2H)，3.95(s,3H)。

MS(ESI):572.2[M+H] ⁺。

Embodiment 56: prepare compound 52

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 223mg yellow solid, compound 52, productive rate 40%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):9.92(t,1H),8.15(d,1H),7.80(d,1H),7.70(m,3H),7.40(m,2H),7.20(m,2H),6.45(s,2H),6.06(d,2H),5.95(d,1H),3.95(s,3H)。

MS(ESI):498.1[M+H] ⁺。

Embodiment 57: prepare compound 53

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 508mg yellow solid, compound 53, productive rate 66%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.60(d,1H),8.55(t,1H),8.15(d,1H),7.60(m,3H),7.50(d,1H),7.45(m,2H),7.38(m,2H),7.16(t,2H),6.05(d,1H),4.45(d,2H)，4.25(t,2H)，4.05(s,3H)，3.92(s,3H)，3.60(t,4H)，2.42(m,4H)，2.00(m,2H)。

MS(ESI):687.2[M+H] ⁺。

Embodiment 58: prepare compound 54

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 337mg yellow solid, compound 54, productive rate 65%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.65(t,1H),8.55(d,1H),8.22(d,1H),8.15(d,1H),7.75(d,1H),7.68(m,2H),7.45(m,1H),7.38(m,2H),7.15(t,2H),6.75(d,1H),6.05(d,2H),4.45(d,2H)，3.95(s,3H)。

MS(ESI):519.1[M+H] ⁺。

Embodiment 59: prepare compound 55

Take the compound 68 that 450mg is about 1.12mmol, according to the method for embodiment 45, through two-step reaction, obtain 384mg yellow solid, compound 55, productive rate 50%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.55(t,1H),8.15(d,1H),7.65(m,1H),7.55(m,1H),7.52(d,1H),7.45(m,2H),7.38(m,2H),7.13(t,2H),6.58(d,1H),6.05(d,1H),4.45(t,2H)，4.21(s,3H)，3.92(s,3H)，3.60(t,4H)，2.40(m,4H)，2.00(m,2H)。

MS(ESI):686.3[M+H] ⁺。

Embodiment 60: prepare compound 56

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 331mg yellow solid, compound 56, productive rate 52%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):11.84(s,1H),8.34(dd,1H),7.89(dd,1H),7.77(dd,1H),7.51(d,1H),7.22(m,3H),7.09(t,1H),6.50(t,1H),6.17(s,2H),5.69(d,1H)。

MS(ESI):468.1[M+H] ⁺。

Embodiment 61: prepare compound 57

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 351mg yellow solid, compound 57, productive rate 65%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):9.90(s,1H),8.48(dd,1H),8.05(dd,1H),7.83(d,1H),7.77(dd,1H),7.42(m,2H),7.33(m,3H),6.66(t,1H),6.46(s,2H),6.03(d,1H)，4.50(d,2H)。

MS(ESI):482.1[M+H] ⁺。

Embodiment 62: prepare compound 58

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 288mg yellow solid, compound 58, productive rate 55%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):10.10(s,1H),8.53(d,1H),8.06(d,1H),7.84(d,1H),7.72(d,1H),7.48(m,2H),7.22(m,3H),7.16(m,1H),6.63(d,1H),6.50(s,2H),6.06(d,1H)。

MS(ESI):468.1[M+H] ⁺。

Embodiment 63: prepare compound 59

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 288mg yellow solid, compound 59, productive rate 55%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):10.50(s,1H),7.82(m,4H),7.45(m,2H),7.22(m,2H),7.08(d,1H),6.70(d,1H),6.46(s,2H),6.06(d,1H)。

MS(ESI):468.1[M+H] ⁺。

Embodiment 64: prepare compound 60

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 351mg yellow solid, compound 60, productive rate 65%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):9.95(t,1H),7.85(d,1H),7.77(d,1H),7.45(m,4H),7.28(m,2H),6.90(d,1H),6.66(t,1H),6.46(s,2H),6.20(t,1H)，6.00(d,1H)，5.85(m,1H)，4.50(d,2H)。

MS(ESI):482.1[M+H] ⁺。

Embodiment 65: prepare compound 61

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 355mg yellow solid, compound 61, productive rate 65%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):9.02(s,1H),8.85(t,1H),8.35(d,1H),8.05(d,1H),7.90(d,1H),7.45(m,6H),7.15(t,2H),7.00(d,1H),6.52(d,1H),4.40(d,2H).MS(ESI):488.1[M+H] ⁺.

Embodiment 66: prepare compound 62

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 394mg yellow solid, compound 62, productive rate 72%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):9.00(s,1H),8.88(t,1H),8.65(d,1H),8.35(d,1H),8.28(d,1H),7.98(m,3H),7.45(m,2H),7.35(d,2H),7.15(t,2H),6.55(d,1H),4.42(d,2H)。

MS(ESI):489.1[M+H] ⁺。

Embodiment 67: prepare compound 63

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 425mg yellow solid, compound 63, productive rate 70%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):8.55(d,1H),8.35(t,1H),8.00(m,3H),7.75(m,3H),7.55(d,2H),7.38(m,2H),7.20(s,2H),7.08(t,2H),6.55(d,1H),4.45(d,2H)，4.00(s,6H),3.90(s,3H)。

MS(ESI):543.2[M+H] ⁺。

Embodiment 68: prepare compound 64

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 499mg yellow solid, compound 64, productive rate 72%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):9.65(b,1H),8.95(t,1H),8.55(d,1H),8.35(d,1H),8.00(m,3H),7.50(m,6H),7.20(s,2H),7.08(t,2H),6.50(d,1H),4.42(d,2H)，3.90(s,3H)。

MS(ESI):619.2[M+H] ⁺。

Embodiment 69: prepare compound 65

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 558mg yellow solid, compound 65, productive rate 75%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):9.66(s,1H),8.86(t,1H),8.49(d,1H),8.35(d,1H),7.95(m,3H),7.85(d,1H),7.45(m,2H),7.35(m,2H),7.20(d,1H),7.13(t,2H),6.55(d,1H),4.45(d,2H)，4.23(t,2H)，3.92(s,3H)，3.60(t,4H)，2.40(m,4H)，2.05(m,2H)。

MS(ESI):665.2[M+H] ⁺。

Embodiment 70: prepare compound 66

Take the compound 67 that 450mg is about 1.12mmol, according to the method for embodiment 5, through two-step reaction, obtain 390mg yellow solid, compound 66, productive rate 68%.

The product making is tested, and result is as follows:

H-NMR(300MHz,DMSO-d6):9.15(b,1H),8.85(t,1H),8.45(d,1H),8.35(d,1H),8.25(d,1H),7.95(m,1H),7.49(m,4H),7.35(m,3H),7.15(m,3H),6.92(m,1H),6.53(d,1H),4.42(d,2H)，3.90(s,3H)。

MS(ESI):512.2[M+H] ⁺。

The external biochemistry level arrestin of embodiment 71 kinases (PK) activity experiment

Materials and methods: c-Met, Flt-3, VEGFR-2, PDGFR-β and c-Kit kinases, derive from Invitrogen; HTRF KinEASE; TK kit(Cisbio company); 384 orifice plates (Greiner company); ATP(sigma company), MgCl ₂(sigma) company; The multi-functional microplate reader of PHERAstar FS (BMG company); Low speed centrifuge (StaiteXiangyi company); Thermostat container (Binder company).

Compound dissolution and preservation: depending on solvability, with DMSO, test-compound is configured to the mother liquor of 0.5-10mmol/L ,-20 ℃ of preservations after packing;

The preparation of compound working fluid: before test, the compound of packing is taken out from refrigerator, be diluted to 50 * desired concn with pure DMSO; Then with deionized water by diluted chemical compound to 4 * desired concn;

The preparation of 1.33 * Enzymatic buffer: 5 * Enzymatic buffer is derived to HTRF kit) with deionized water be diluted to 1.33 *, and add the corresponding composition of 1.33 * final concentration: 1.33mmol/L DTT and 1.33mmol/L MgCl ₂;

The preparation of kinases working fluid: Met is diluted to 2 * required final concentration 0.2ng/ μ L with 1.33 * Enzymatic buffer;

The preparation of substrate working fluid: substrate-biotin(is derived to HTRF kit with 1.33 * Enzymatic buffer) and ATP(10mmol/L) dilution is the mixed solution of 4 * required final concentration;

The preparation of testing liquid: with HTRF detection buffer, the Streptavidin-XL665 of 16.67 μ mol/L is diluted to 4 * required final concentration, then mixes (all deriving from HTRF kit) with isopyknic Antibody-Cryptate.

Enzyme reaction step: the kinases working fluid to adding 4 μ L in each hole of low volume 384 microwell plates adds 1.33 * Enzymatic buffer of 4 μ L as negative control (Negative) simultaneously; The compound working fluid that adds 2 μ L to hole, as pulverised compound concentration, contrast (is positive control, Positive) to the 8%DMSO aqueous solution that simultaneously adds 2 μ L; In 25 ℃ (or 30 ℃), hatch 5-10min; Xiang Kongzhong adds 2 μ L substrate working fluids to start enzyme reaction, in 25 ℃ of (or 30 ℃) oscillatory reaction 15-60min.

HTRF reagent detecting step: the testing liquid termination reaction that adds 8 μ L to hole; 25 ℃ of reaction 1h;

Reading of HTRF signal: adopt PHERAstar FS reading detection signal, instrument arrange accordingly is as follows:

Optic?module

Integration?delay(lag?time)50μs

Integration?time400μs

Number?of?flashes200

The raw data of reading for every hole, ratio=665nm/620nm;

The calculating of inhibiting rate:

IC ₅₀the calculating of value: the logarithm of compound concentration of take is X-coordinate, inhibiting rate is ordinate zou, in GraphPad Prism5, matching nonlinear curve: log (inhibitor) vs.response--Variable slope, obtains the enzyme testing compound concentration IC of inhibiting rate while being 50% that live ₅₀.

Experimental result: c-Met kinase activity half-inhibition concentration (IC ₅₀nmol/L)

The invention provides structure suc as formula compound shown in I the half-inhibition concentration (IC to c-Met kinase activity ₅₀) in Table 1:

Half-inhibition concentration (the IC of table 1 compound to c-Met kinase activity ₅₀)

IC ₅₀<500nmol/L+++；500-5000nmol/L++；>5000nmol/L+。

The embodiment 72 horizontal arrestin kinases of cell in vitro (PK) activity experiments

Materials and methods: people's gastric adenocarcinoma cells strain MKN-45 etc. all derives from Chinese Academy of Sciences's Shanghai cell bank; 1640 substratum (GIBCO company); Foetal calf serum (GIBCO company); 24 porocyte culture plates (Costar company); 96 hole water white transparency high-affinity enzyme plates (Costar company); HGF(R & DSystem company); Cell pyrolysis liquid (green the skies company); C-Met capture antibody(R & D System company); Anti-phosphotyrosine antibody, clone4G10(Upstate company); Company of HRP labeled goat-anti-mouse antibody(Zhong Shan Golden Bridge); TMB(Pierce company); Enzyme mark detector (Tecan company, Infinite M200); Multifunctional plate washing machine (Bio-Rad company)

Compound configuration: positive drug and each test-compound are configured to the mother liquor of 10mmol/L with DMSO ,-20 ℃ of preservations.

Met antibody is coated: C-met antibodies is diluted to 2 μ g/mL, adds in enzyme plate 4 ℃ coated spend the night (16-18h) with the amount of every hole 100 μ L.PBST(PBS/0.05%Tween20, pH7.4) wash 3 times; Every hole adds confining liquid (5%BSA/PBS) 200 μ L, 37 ℃ of sealing 2h; PBST washing 3 times; Capture c-Met albumen: in 24 porocyte culture plates, inoculate the MKN-45 cell of 80-90% degrees of fusion, after 8-10h cell attachment, change serum-free 1640 substratum, hunger is spent the night; Compound with serum-free 1640 substratum gradient dilutions; Suck substratum in 24 orifice plates, add fast 180 μ L/ hole compound concentration gradient dilution liquid, and the cell of compound effects is hatched to 1h at incubator; With serum-free 1640 substratum, HGF is configured to the solution of 800ng/mL, in 24 orifice plates, every hole adds 20 μ L, after slightly mixing, at 37 ℃, stimulates 5-8min; Suck fast substratum supernatant in 24 orifice plates, every hole adds 240 μ LRIPA lysates; In enzyme plate after sealing, every hole adds 100 μ l cell pyrolysis liquids, 37 ℃ of 100rpm jolting 2h; PBST washing 3 times;

The detection of Phosphotyrosine: primary antibodie is hatched, every hole adds 100 μ L mouse source Anti-phosphotyrosine antibody, Clone4G10(0.5%BSA/PBS(W/V) 1:2000 dilution), 37 ℃ of 100rpm jolting 1-1.5h; PBST washing 3 times; Two anti-hatching: every hole adds 100 μ L HRP goat anti mouse IgG(0.5%BSA/PBS(W/V) 1:3000 doubly dilutes), 37 ℃ of 100rpm jolting 1h; PBST washing 6 times; Tmb substrate colour developing: every hole adds 100 μ L TMB substrate, room temperature darkroom reflection 2-10min; After substrate arrives suitable color, every hole adds 50mL2mol/L H ₂sO ₄; Microplate reader 450nm absorbing wavelength place measures light absorption value.

Two control groups, negative control group are established in experiment: add the SCR-1 of 10-5mol/L high density, not adding HGF stimulates; Positive controls: do not add any medicine, only adding HGF stimulates;

The mean value that calculates all administration groups and control group, calculates inhibiting rate as follows:

Experimental result: the half-inhibition concentration scope (IC of part of compounds of the present invention to c-Met kinases cell levels activity ₅₀) in Table 2:

Half-inhibition concentration scope (the IC of table 2 compound to c-Met kinases cell levels activity ₅₀)

IC ₅₀<1μmol/L+++；1-10μmol/L++；>10μmol/L+。

The measuring method (mtt assay) of embodiment 73 compound inhibition tumor cell propagation provided by the invention

Reagent and instrument:

RPMI1640 substratum (RPMI1640+12% calf serum+HEPES3.5g/L+NaHCO ₃2.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);

RPMI1640 substratum (RPMI1640+12% foetal calf serum+HEPES3.5g/L+NaHCO ₃2.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);

DMEM in high glucose substratum (DMEM+10% calf serum+HEPES3.5g/L+NaHCO ₃2.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);

DMEM in high glucose substratum (DMEM+12% foetal calf serum+HEPES3.5g/L+NaHCO ₃2.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);

MC COYS5-A substratum (DMEM+12% foetal calf serum+HEPES3.5g/L+NaHCO ₃2.2g/L+ penicillin 0.13g/L+ Streptomycin sulphate 0.15g/L);

Trypsinase; MTT(U.S. Amresco company product); Microplate reader (TECAN infinite M200)

People's gastric adenocarcinoma cells strain (BGC); Non-small cell lung carcinoma (A549); Human leukemia cell line (K562); Human pancreas cancer cell strain (PANC-1); Human small cell lung carcinoma (NCI-H446); RPMI1640 substratum containing 12% calf serum for listed JEG-3, in 37 ℃, 5%CO ₂incubator in cultivate;

Human pancreas cancer cell strain (BXPC-3); Human bladder cancer cell's strain (T24); The RPMI1640 substratum of 12% foetal calf serum for listed JEG-3, in 37 ℃, 5%CO ₂incubator in cultivate;

Human hepatoma cell strain (HEPG2); Human breast cancer cell strain (MCF-7); The DMEM in high glucose substratum of 12% calf serum for listed JEG-3, in 37 ℃, 5%CO ₂incubator in cultivate;

Human colon adenocarcinoma cell's strain (CACO-2), with the DMEM in high glucose substratum of 12% foetal calf serum, in 37 ℃, 5%CO ₂incubator in cultivate;

Human colon cancer cell strain (HT29); Human colon cancer cell strain (HCT116); Human oophoroma cell line (SK-OV-3); The MC COYS5-A substratum of 12% foetal calf serum for listed JEG-3, in 37 ℃, 5%CO ₂incubator in cultivate.

Inoculation: get in exponential phase of growth, one bottle, cell in good condition, adds appropriate tryptic digestive juice, digestion comes off attached cell, with containing RPMI1640(or DMEM or the 5A of 12% calf serum) nutrient solution is made into cell suspension, counting, and cell density adjustment is diluted to 1.67 * 10 ⁴/ mL obtained cell suspension is inoculated on 96 orifice plates, 180 μ L/ holes (containing tumour cell 3000/ hole).

Cultivate: culture plate is proceeded to constant temperature CO ₂in incubator, at 37 ℃, 5%CO ₂and under saturated humidity condition, cultivate 24 hours.

Primary dcreening operation: testing compound is first mixed with 0.1mol/L concentration with DMSO, remakes 3 extent of dilution, and for primary dcreening operation, concentration is followed successively by 10 ^-5mol/L, 10 ^-6mol/L and 10 ^-7mol/L.Add testing compound, 20 μ L/ holes, cultivate 72 hours.Establish 3 parallel holes for every group, and repeat 3 times, measure the 96 every hole of orifice plate light absorption values, record result and calculate inhibitory rate of cell growth, get mean value three times.

Dyeing: MTT is added in 96 orifice plates (attached cell), and 20 μ L/ holes, are placed in incubator and hatch 4 hours, inhales and abandons supernatant liquor in hole, adds DMSO100 μ L/ hole, on horizontalization plate shaking table, shakes 5 minutes.MTT is added to (suspension cell) in 96 orifice plates, and 20 μ L/ holes, are placed in incubator and hatch 4 hours, then add 20%SDS50 μ L/ hole, are placed in incubator and spend the night.

Measure: it is 570nm that microplate reader is set wavelength, and reference wavelength is 630nm, measure the 96 every hole of orifice plate light absorption values, record result and calculate inhibitory rate of cell growth, to judge the anti-tumor activity of tested medicine.

Multiple sieve: be 10 in primary dcreening operation concentration ^-5during mol/L, the compound of 3 cell inhibitory rate>=50%, for multiple sieve, remakes 10 extent of dilution by 0.1mol/L, and concentration is followed successively by 10 ^-5mol/L, 0.5 * 10 ^-5mol/L, 10 ^-6mol/L, 0.8 * 10 ^-6mol/L, 0.6 * 10 ^-6mol/L, 0.4 * 10 ^-6mol/L, 0.2 * 10 ^-6mol/L, 10 ^-7mol/L, 0.8 * 10 ^-7mol/L and 0.4 * 10 ^-7mol/L.Add test-compound, 20 μ L/ holes, cultivate 48 hours.Establish 3 parallel holes for same every group, and repeat 3 times, and according to prescreening method, measure the 96 every hole of orifice plate light absorption values, record result and calculate inhibitory rate of cell growth.

Inhibitory rate of cell growth and IC ₅₀calculating:

Simultaneously according to the growth inhibition ratio of each concentration, adopt logarithm with compound concentration with Logit linear regression, obtain the testing compound concentration IC when suppressing growth rate and being 50% ₅₀, get mean value three times.

Test-results: in the embodiment of the present invention 5 to 70, the compound with formula I structure of preparation is inhibited to the propagation of kinds of tumor cells, statistical analysis, effect is (P<0.05) significantly, its IC ₅₀all 10 ^-5below mol/L.

The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.

Claims

1. compound, its pharmacy acceptable salt, described compound is:

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 3-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the chloro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides (I-4)

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 2-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the chloro-benzyl of 3-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-cyano group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-benzyl-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(3-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-trifluoromethyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-methoxyl group-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(4-methyl-benzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the chloro-3-trifluoromethyl-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-phenyl)-N-(the fluoro-benzyl-6-of 4-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-isobutyl--6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-tertiary butyl-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-sec.-propyl-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-(2-cyano ethyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) the fluoro-phenyl of oxo-3-)-N-(2-cyano methyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(2-cyano methyl)-N-(4-luorobenzyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-5-1,2,3,4-tetrahydroisoquinoline-2-carbonyl) pyridine-2 (1H) ketone

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(furans-2-ylmethyl)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-alkynyl pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(3-hydroxyl third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(3-dimethylamino third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-methylol-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((dimethylamino methyl-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-(morpholinyl-methyl)-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-(piperidin-1-yl-methyl)-1H-pyrroles [2,3-b] pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the fluoro-4-of 3-(thiophene [3,2-d] pyrimidine-4-yl) oxo-phenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the fluoro-4-of 3-(thiophene [3,2-b] pyridin-7-yl) oxo-phenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-(6,7-dimethoxyquinazoline-4-yl) the fluoro-phenyl of oxo 3-)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-(6-benzyloxy-7-methoxyl group quinazoline-4-yl) the fluoro-phenyl of oxo 3-)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the fluoro-4-of 3-(7-methoxyl group-6-(morpholinyl-propoxy--quinazoline-4-yl) oxo-phenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

5 '-((2-amino-3-chloropyridine-4-yl) oxo-N-(the fluoro-benzyl of 4-)-2-oxo-2H[1,2-dipyridyl]-5-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo phenyl)-N-(the fluoro-benzyl of 4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-4-oxyethyl group-6-oxo-1,6-dihydropyridine-3-acid amides

4-allyloxy-1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-4-oxyethyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-4-(2-methoxyethoxy)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-4-(2,3-dihydroxyl propoxy-)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-4-(2-methoxyethoxy)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(3-hydroxyl third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-4 methoxyl groups-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(3-dimethylamino third-1-alkynes-1-yl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-(4-fluorophenyl) pyridin-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-iodine pyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-phenyl of 4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the fluoro-4-of 3-(7-methoxyl group-6-(morpholinyl-propoxy--quinazoline-4-yl) oxo-phenyl)-N-(the fluoro-benzyl of 4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the fluoro-4-of 3-(thiophene [3,2-b] pyridin-7-yl) oxo-phenyl)-N-(the fluoro-benzyl of 4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the fluoro-4-of 3-(6-methoxyl group-7-(morpholinyl-propoxy--quinolyl-4) oxo-phenyl)-N-(the fluoro-benzyl of 4-)-4-methoxyl group-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-phenyl of 4-)-2-oxo-1,2-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-phenyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-((2-amino-3-chloropyridine-4-yl) oxo-3-fluorophenyl)-N-(the fluoro-benzyl of 4-)-2-oxo-1,2-dihydropyridine-3-acid amides

1-(the fluoro-4-of 3-(thiophene [3,2-b] pyridin-7-yl) amino-phenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the fluoro-4-of 3-(thiophene [3,2-d] pyrimidine-4-yl) amino-phenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-(6,7-dimethoxyquinazoline-4-yl) the fluoro-phenyl of amino 3-)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(4-(6-benzyloxy-7-methoxyl group quinazoline-4-yl) the fluoro-phenyl of amino 3-)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(the fluoro-4-of 3-(7-methoxyl group-6-(morpholinyl-propoxy--quinazoline-4-yl) amino-phenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides

1-(3-fluoro-((7-methoxy quinoline-4-yl) amino-phenyl)-N-(the fluoro-benzyl of 4-)-6-oxo-1,6-dihydropyridine-3-acid amides.

2. the purposes of compound as claimed in claim 1 in the medicine for the preparation for the treatment of mammalian proteins kinase-associated conditions, described protein kinase related disorder is selected from squamous cell carcinoma, stellate cell cancer, Kaposi's sarcoma, spongioblast cancer, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, mammary cancer, neurospongioma, colorectal carcinoma, liver cancer, kidney, genitourinary cancer, carcinoma of the pancreas or gastrointestinal cancer, diabetes, excess proliferative disease, blood vessel generation, inflammatory diseases, immunological disease or cardiovascular disorder.